Doses Of Naloxone Research Articles

Steep increases in fentanyl-related mortality west of the Mississippi River: Recent evidence from county and state surveillance

BackgroundOverdose deaths from synthetic opioids (e.g., fentanyl) increased 10-fold in the United States from 2013 to 2018, despite such opioids being rare in illicit drug markets west of the Mississippi River. Public health professionals have feared a “fentanyl breakthrough” in western U.S. drug markets could further accelerate overdose mortality. We evaluated the number and nature of western U.S. fentanyl deaths using the most recent data available. MethodsWe systematically searched jurisdictions west of the Mississippi River for publicly available data on fentanyl-related deaths since 2018, the most recent Centers for Disease Control and Prevention (CDC) statistics. Using mortality data from 2019 and 2020, we identified changes in fentanyl-related mortality rate and proportion of fatal heroin-, stimulant, and prescription pill overdoses involving fentanyl. ResultsSeven jurisdictions had publicly available fentanyl death data through December 2019 or later: Arizona; California; Denver County, CO; Harris County, TX; King County, WA; Los Angeles County, CA; and Dallas-Fort Worth, TX (Denton, Johnson, Parker, and Tarrant counties). All reported increased fentanyl deaths over the study period. Their collective contribution to national synthetic narcotics mortality increased 371 % from 2017 to 2019. Available 2020 data shows a 63 % growth in fentanyl-mortality over 2019. Fentanyl-involvement in heroin, stimulant, and prescription pill deaths has substantially grown. DiscussionFentanyl has spread westward, increasing deaths in the short-term and threatening to dramatically worsen the nation’s already severe opioid epidemic in the long-term. Increasing the standard dose of naloxone, expanding Medicaid, improving coverage of addiction treatment, and public health educational campaigns should be prioritized.

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.

Blocking Opioid Receptors in a Songbird Cortical Region Modulates the Acoustic Features and Levels of Female-Directed Singing.

The organization of the anterior forebrain pathway (AFP) of songbirds important for context-dependent singing is similar to that of cortical basal ganglia loops (CBG) in mammals, which underlie motor behaviors including vocalization. Since different components of the AFP express high levels of μ-opioid receptors (μ-ORs) as do CBG loops, songbirds act as model systems to study the role of opioid modulation on vocalization and the motivation to sing. The AFP in songbirds includes the cortical/pallial region LMAN (lateral magnocellular nucleus of the anterior nidopallium) which projects to Area X, a nucleus of the avian basal ganglia. In the present study, microdialysis was used to infuse different doses of the opioid antagonist naloxone in LMAN of adult male zebra finches. Whereas all doses of naloxone led to significant decreases in the number of FD (female-directed) songs, only 100 and 200 ng/ml of naloxone affected their acoustic properties. The decrease in FD song was not accompanied by changes in levels of attention toward females or those of neurotransmitters (dopamine, glutamate, and GABA) in LMAN. An earlier study had shown that similar manipulations in Area X did not lead to alterations in the number of FD songs but had significantly greater effects on their acoustic properties. Taken together, our results suggest that there are reciprocal effects of OR modulation on cortical and basal ganglia components of the AFP in songbirds.

Prehospital naloxone administration \u2013 what influences choice of dose and route of administration?

BackgroundAmidst the ongoing opioid crisis there are debates regarding the optimal route of administration and dosages of naloxone. This applies both for lay people administration and emergency medical services, and in the development of new naloxone products.We examined the characteristics of naloxone administration, including predictors of dosages and multiple doses during patient treatment by emergency medical service staff in order to enlighten this debate.MethodsThis was a prospective observational study of patients administered naloxone by the Oslo City Center emergency medical service, Norway (2014–2018). Cases were linked to The National Cause of Death Registry. We investigated the route of administration and dosage of naloxone, clinical and demographic variables relating to initial naloxone dose and use of multiple naloxone doses and one-week mortality.ResultsOverall, 2215 cases were included, and the majority (91.9%) were administered intramuscular naloxone. Initial doses were 0.4 or 0.8 mg, and 15% of patients received multiple dosages. Unconscious patients or those in respiratory arrest were more likely to be treated with 0.8 mg naloxone and to receive multiple doses. The one-week mortality from drug-related deaths was 4.1 per 1000 episodes, with no deaths due to rebound opioid toxicity.ConclusionsIntramuscular naloxone doses of 0.4 and 0.8 mg were effective and safe in the treatment of opioid overdose in the prehospital setting. Emergency medical staff appear to titrate naloxone based on clinical presentation.

Overdose Education and Naloxone Distribution Within Syringe Service Programs - United States, 2019.

Syringe service programs (SSPs), which provide access to sterile syringes and other injection equipment and their safe disposal after use,* represent a highly successful human immunodeficiency virus (HIV) prevention intervention. SSPs are associated with a 58% reduction in the incidence of HIV infection among persons who inject drugs (1). In addition, SSPs have led efforts to prevent opioid overdose deaths by integrating evidence-based opioid overdose education and naloxone distribution (OEND) programs (2-4). OEND programs train laypersons to respond during overdose events and provide access to naloxone and directions for drug delivery (2-4). SSPs are ideal places for OEND because they provide culturally relevant services designed to reach persons at high risk for experiencing or observing an opioid overdose. A 2013 survey found that only 55% of SSPs in the United States had implemented OEND (5). To characterize current implementation of OEND among SSPs, and to describe the current reach (i.e., the ratio of persons who received naloxone per opioid overdose death and the ratio of naloxone doses distributed per opioid overdose death) of SSP-based OEND programs by U.S. Census division,† a survey of known U.S. SSPs was conducted in 2019, which found that 94% of SSPs had implemented OEND. In addition, the reach of SSP-based OEND programs varied by U.S. Census division. Scaling up of SSP-based OEND delivery programs could be a critical component for areas of the country with high opioid overdose death rates and low reach.

Slow-sustained delivery of naloxone reduces typical naloxone-induced precipitated opioid withdrawal effects in male morphine-dependent mice.

Thousands of individuals die each year from opioid-related overdoses. While naloxone (Narcan®) is currently the most widely employed treatment to reverse opioid toxicity, high or repeated doses of this antidote often lead to precipitated opioid withdrawal (POW). We hypothesized that a slow linear release of naloxone from a nanoparticle would induce fewer POW symptoms compared to high-dose free naloxone. First, we measured the acute impact of covalent naloxone nanoparticles (Nal-cNPs) on morphine-induced antinociception in the hotplate test. We found that Nal-cNP treatment blocked the antinociceptive effect of morphine within 15min of administration. Next, we tested the impact of Nal-cNPs on POW symptoms in male morphine-dependent mice. To induce morphine dependence, mice were treated with 5mg/kg morphine (or saline) twice-daily for six consecutive days. On day 7 mice received 5mg/kg morphine (or saline) injections 2hr prior to receiving treatment of either unmodified free naloxone, a high or low dose of Nal-cNP, empty nanoparticle (cNP-empty), or saline. Behavior was analyzed for 0-6hr followed by 24 and 48hr time points after treatment. As expected, free naloxone induced a significant increase in POW behavior in morphine-dependent mice compared to saline-treated mice upon free naloxone administration. In comparison, reduced POW behavior was observed with both doses of Nal-cNP. Side effects of Nal-cNP on locomotion and fecal boli production were measured and no significant side-effects were observed. Overall, our data show that sustained release of naloxone from a covalent nanoparticle does not induce severe POW symptoms in morphine-dependent mice.

Layperson reversal of opioid overdose supported by smartphone alert: A prospective observational cohort study.

BackgroundRapid naloxone administration is crucial in reversing an opioid overdose. We investigated whether equipping community members, including people who use opioids (PWUO), with a smartphone application enabling them to signal and respond to suspected overdose would support naloxone administration in advance of Emrgency Medical Services (EMS).MethodsThis observational cohort study of opioid overdose intervention used a dedicated smartphone app, UnityPhilly, activated by volunteers witnessing an overdose to signal other nearby volunteers in Philadelphia (March 2019 - February 2020). Alerted volunteers chose to respond, or declined to respond, or ignored/missed the alert. Witnessing volunteer was connected to 9-1-1 through a semi-automated telephone call. The primary outcome was layperson-initiated overdose reversal before EMS arrival, and a secondary outcome was hospital transfer. This study is registered with ClinicalTrials.gov, NCT03305497.Findings112 volunteers, including 57 PWUO and 55 community members, signaled 291 suspected opioid overdose alerts. 89 (30⸱6%) were false alarms. For 202 true alerts, the rate of layperson initiated naloxone use was 36⸱6% (74/202 cases). Most naloxone-use cases occurred in the street (58⸱11% (43/74)) and some in home settings (22⸱98% (17/74)). The first naloxone dose was provided by a nearby volunteer responding to the alert in 29⸱73% (22/74) of cases and by the signaling volunteer in 70⸱27% (52/74) of cases. Successful reversal was reported in 95⸱9% (71/74) of cases. Layperson intervention preceded EMS by 5 min or more in 59⸱5% of cases. Recovery without hospital transport was reported in 52⸱7% (39/74) of cases.InterpretationOur findings support the benefits of equipping community members, potentially witnessing suspected opioid overdose, with naloxone and an emergency response community smartphone app, alerting EMS and nearby laypersons to provide additional naloxone.FundingFunding provided by NIH through NIDA, grant number: 5R34DA044758.

Higher naloxone dosing in a quantitative systems pharmacology model that predicts naloxone-fentanyl competition at the opioid mu receptor level.

Rapid resuscitation of an opioid overdose with naloxone, an opioid antagonist, is critical. We developed an opioid receptor quantitative systems pharmacology (QSP) model for evaluation of naloxone dosing. In this model we examined three opioid exposure levels that have been reported in the literature (25 ng/ml, 50 ng/ml, and 75 ng/ml of fentanyl). The model predicted naloxone-fentanyl interaction at the mu opioid receptor over a range of three naloxone doses. For a 2 mg intramuscular (IM) dose of naloxone at lower fentanyl exposure levels (25 ng/ml and 50 ng/ml), the time to decreasing mu receptor occupancy by fentanyl to 50% was 3 and 10 minutes, respectively. However, at a higher fentanyl exposure level (75 ng/ml), a dose of 2 mg IM of the naloxone failed to reduce mu receptor occupancy by fentanyl to 50%. In contrast, naloxone doses of 5 mg and 10 mg IM reduced mu receptor occupancy by fentanyl to 50% in 5.5 and 4 minutes respectively. These results suggest that the current doses of naloxone (2 mg IM or 4 mg intranasal (IN)) may be inadequate for rapid reversal of toxicity due to fentanyl exposure and that increasing the dose of naloxone is likely to improve outcomes.

Comparison of rates of opioid withdrawal symptoms and reversal of opioid toxicity in patients treated with two naloxone dosing regimens: a retrospective cohort study

Introduction When managing opioid overdose (OD) patients, the optimal naloxone regimen should rapidly reverse respiratory depression while avoiding opioid withdrawal. Published naloxone administration guidelines have not been empirically validated and most were developed before fentanyl OD was common. In this study, rates of opioid withdrawal symptoms (OW) and reversal of opioid toxicity in patients treated with two naloxone dosing regimens were evaluated. Methods In this retrospective matched cohort study, health records of patients who experienced an opioid OD treated in two urban emergency departments (ED) during an ongoing fentanyl OD epidemic were reviewed. Definitions for OW and opioid reversal were developed a priori. Low dose naloxone (LDN; ≤0.15 mg) and high dose naloxone (HDN; >0.15 mg) patients were matched in a 1:4 ratio based upon initial respiratory rate (RR). The proportion of patients who developed OW and who met reversal criteria were compared between those treated initially with LDN or HDN. Odds ratios (OR) for OW and opioid reversal were obtained via logistic regression stratified by matched sets and adjusted for age, sex, pre-naloxone GCS, and presence of non-opioid drugs or alcohol. Results Eighty LDN patients were matched with 299 HDN patients. After adjustment, HDN patients were more likely than LDN patients to have OW after initial dose (OR = 8.43; 95%CI: 1.96, 36.3; p = 0.004) and after any dose (OR = 2.56; 95%CI: 1.17, 5.60; p = 0.019). HDN patients were more likely to meet reversal criteria after initial dose (OR = 2.73; 95%CI: 1.19, 6.26; p = 0.018) and after any dose (OR = 6.07; 95%CI: 1.81, 20.3; p = 0.003). Conclusions HDN patients were more likely to have OW but also more likely to meet reversal criteria versus LDN patients.

Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594.

Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4β2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam. Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague-Dawley rats. Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam. Activation of α4β2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.

An open-label, randomized, single-dose, two-period, two-treatment crossover bioavailability study comparing 5 mg/0.5 mL of intramuscular naloxone hydrochloride to 2 mg/0.4 mL intramuscular naloxone hydrochloride autoinjector in healthy subjects.

Naloxone is an opioid antagonist used for the acute treatment of opioid overdoses. There has been a dramatic increase of deaths due to synthetic opioids such as fentanyl, some requiring multiple doses of naloxone for reversal of opioid tox-icity. Fentanyl appears to differ from other opiates as having a very rapid onset and transport in and out of the central nervous system (CNS). Fentanyl is therefore widely distributed in the CNS. Furthermore, a high range of systemic levels of fentanyl have been observed in overdose victims. Taken together, we believe it is very likely that higher doses of naloxone are needed to combat this new era of overdoses. We examined the bioavailability of an investigational 5 mg intramuscular naloxone in a prefilled syringe (PFS) compared to 2 mg intramuscular naloxone in an autoinjector (AI) at the current approved dose in a crossover design which included 14 healthy subjects. Overall, both doses were well tol-erated with no adverse events noted during the trial. The pharmacokinetic results showed that a higher dose of intra-muscular naloxone hydrochloride increases Cmax, AUC, and t1/2; however, Tmax was similar for both treatments. Statistical analysis indicated that there were statistical differences between the test and reference treatments for Cmax, AUCs, and t1/2 with ratios of test to reference for Cmax of 337.1 percent (CI: 263.3 percent, 431.5 percent), AUC0-t of 277.5 percent (CI: 260.4 percent, 295.7 percent), AUC0-inf of 273.4 percent (CI: 255.6 percent, 292.4 percent), and t1/2 of 110.5 percent (CI: 95.5, 127.9). These results are consistent with the study rationale that indicated higher doses of intramuscular naloxone hy-drochloride would result in higher Cmax and AUCs. These PK characteristics may be desirable for reversing opioid toxicity caused by the higher, more potent synthetic opioids.

P131: Practice patterns of emergency department physicians administering naloxone for patients with suspected opioid overdose

Introduction: Naloxone is recommended for reversing opioid-associated respiratory depression. There is wide variability in emergency department (ED) practice patterns regarding naloxone use, dosing, and observation time post-administration. This study describes the naloxone practice patterns of ED physicians managing suspected opioid overdose patients. Methods: A retrospective chart review was conducted of adult patients (≥ 18 years) presenting to an academic tertiary care centre (consisting of two EDs with an annual census 150,000 visits) in 2017 with suspected opioid overdose who were administered naloxone in the ED. Patients were identified electronically and the following information was abstracted from patient charts: demographics, naloxone dosage and infusion initiation, disposition data, indications for naloxone administration, response to therapy, and adverse effects. Variability in initial and total dose was examined. Initial dose was also compared in those with cardiorespiratory compromise (CPR given, respiratory rate &lt; 8, or desaturation below 89%) using independent samples median tests. Data was analyzed using standard descriptive statistics. Results: 113 patients met inclusion criteria. Indications for naloxone administration were: level of consciousness (50.5%), respiratory depression (4.0%), miosis (1.0%), a combination of factors (19.8%), or undocumented (24.8%). Median initial dose was 0.40 mg (IQR: 0.20-0.40 mg). Median total naloxone administered in the ED was 0.48 mg (IQR: 0.35-1.2 mg). The initial dose resulted in a response in 43.1% of patients, with 36.0% of responding patients later experiencing subsequent respiratory depression. 31% of patients received a naloxone infusion. Initial dose in patients with cardiopulmonary compromise was significantly different only comparing patients who received CPR versus those who did not (median 0.40 mg; IQR: 0.20-0.80 mg; P = 0.019). Four patients experienced emesis following naloxone. Median length of ED stay was 7.0 hours (IQR: 4.0-9.5 hours), and median hospital length of stay was 3.0 days (IQR: 1.0-5.0 days). Median ED observation time prior to discharge was 4.0 hours (IQR: 2.0-8.0 hours). Ultimate disposition home, to the ward, or to the intensive care unit was 47.1%, 42.2%, and 9.8% respectively (1.0% deceased). Conclusion: The dose and usage of naloxone by ED physicians in this study is variable. Further prospective studies are needed to determine the effective naloxone dosing strategy.

Relapse rates among veterans on maintenance doses of combination buprenorphine and naloxone for opioid use disorder.

IntroductionOpioid use disorder (OUD) can cause significant morbidity and mortality with more than 115 people dying from an opioid overdose daily in the United States. Treatment with buprenorphine/naloxone (BUP/NAL) can be effective; however, there is conflicting evidence on the utility of higher doses in preventing relapse. This study was designed to assess BUP/NAL maintenance doses and the rate of relapse in veterans with OUD.MethodsPatients diagnosed with OUD who received a prescription for BUP/NAL through the substance use disorder recovery program were retrospectively evaluated. Patients were categorized into 2 treatment groups: those prescribed ≤16 mg of BUP/NAL daily and those prescribed >16 mg of BUP/NAL daily. The primary outcome was to determine rates of relapse between maintenance doses of BUP/NAL. Secondary outcomes included evaluating the difference in rates of relapse between daily versus take-home dosing, tablets versus films, time to relapse, and use of illicit substances during treatment.ResultsPatients prescribed >16 mg of BUP/NAL daily had statistically significantly lower rates of relapse compared to patients prescribed ≤16 mg of BUP/NAL daily (P = .0018). Regarding secondary outcomes, there was a statistically significant difference in time to relapse (P = .036) and dosage form (P = .0124). Difference in administration of dose and illicit substance use during treatment were not statistically significant.DiscussionThis study identified that rate of relapse can be lowered and time to relapse can be lengthened when doses >16 mg of BUP/NAL are prescribed in the veteran population for OUD.

Patients With OUD Save Lives With Naloxone

Back to table of contents Previous article Next article Clinical & ResearchFull AccessPatients With OUD Save Lives With NaloxoneTerri D'ArrigoTerri D'ArrigoSearch for more papers by this authorPublished Online:13 Apr 2020https://doi.org/10.1176/appi.pn.2020.4a6AbstractProviding take-home naloxone to a patient with opioid use disorder (OUD) enables friends or loved ones to save the patient’s life in the event of an overdose—but sometimes it’s not the patient who overdoses.Giving take-home naloxone to patients in treatment for opioid use disorder (OUD) is an effective harm-reduction strategy that can save lives, a one-year prospective study in JAMA Network Open suggests. But there is a twist: The patients may end up using the naloxone to reverse overdose in someone else, rather than having someone else administer it to them for an overdose.The study included 395 patients with OUD enrolled at the University of New Mexico Addiction and Substance Abuse Opioid Treatment Program, an outpatient clinic. All patients were treated with buprenorphine, methadone, or naltrexone and were given two doses of take-home naloxone combined with opioid overdose education. By the study’s end, 73 of the participants (18%) had used naloxone to perform 114 opioid reversals in the community, all of which were related to heroin. Of those, 86.6% said that they had used their naloxone to reverse an overdose in a friend, relative, acquaintance, or significant other.It should be required to provide overdose education and take-home naloxone to all patients in treatment for OUD.—Joanna G. Katzman, M.D., M.S.P.H.“We see providing take-home naloxone as a significant, strategic, targeted response,” lead author Joanna G. Katzman, M.D., M.S.P.H., a professor in the Department of Neurosurgery at the University of New Mexico School of Medicine in Albuquerque, told Psychiatric News. “If you are going to choose one area in the whole clinical system to provide naloxone, your best bang for the buck is an opioid treatment program.”Katzman should know. She and her colleagues had conducted a similar study with patients at the University of New Mexico Pain Center several years ago, and none of the 164 patients in the study had an opioid overdose or used their naloxone kits to perform an overdose reversal for someone else. The study was published online in Substance Abuse on November 1, 2016.“We did that study to show that yes, you can do this [intervention] in the context of pain centers, but that’s a low-risk population, so I thought we would use the same protocol for a study in our sister clinic—the addiction clinic,” Katzman explained.Katzman said the results indicate a need for policy change, especially because so few patients with OUD are prescribed naloxone: In the year before enrollment, only 4.5% of the patients in the study had received a prescription for the drug.“I feel that it should be mandated that we provide take-home naloxone in the setting of an opioid treatment program. It will help patients and the community by saving lives and keeping families intact, even if it’s not used on them [the patients in treatment],” Katzman said.“If you have a patient with opioid use disorder, strongly consider providing take-home naloxone and overdose education in the clinic,” Katzman added. “This could also apply to emergency room physicians and other clinicians who see patients come in with substance use disorder or a recent opioid overdose, and inpatient clinicians who might be taking care of someone who had an overdose with complications. You may not want to discharge a patient without giving the patient a kit for naloxone.”This research was supported by a grant from Kaleo Pharma, which also donated the Evzio naloxone kits used in the study. ■“Association of Take-Home Naloxone and Opioid Overdose Reversals Performed by Patients in an Opioid Treatment Program” is posted here.“Co-prescription of Naloxone as a Universal Precautions Model for Patients on Chronic Opioid Therapy—Observational Study” is posted here. ISSUES NewArchived

Variations in the California Emergency Medical Services Response to Opioid Use Disorder.

IntroductionOpioids contributed to over 300,000 deaths in the United States in the past 10 years. Most research on drug use occurs in clinics or hospitals; few studies have evaluated the impact of opioid use on emergency medical services (EMS) or the EMS response to opioid use disorder (OUD). This study describes the perceived burden of disease, data collection, and interventions in California local EMS agencies (LEMSA).MethodsWe surveyed medical directors of all 33 California LEMSAs with 25 multiple-choice and free-answer questions. Results were collected in RedCap and downloaded into Excel (Microsoft Corporation, Redmond WA). This study was exempt from review by the Alameda Health System - Highland Hospital Institutional Review Board.ResultsOf the 33 California LEMSAs, 100% responded, all indicating that OUD significantly affects their patients. Most (91%) had specific protocols directing care of those patients and repeat naloxone dosing. After naloxone administration, none permitted release to law enforcement custody, 6% permitted patient refusal of care, and 45% directed base hospital contact for refusal of care. Few protocols directed screening or treatment of OUD or withdrawal symptoms. Regular data collection occurred in 76% of LEMSAs, with only 48% linking EMS data with hospital or coroner outcomes. In only 30% did the medical director oversee regular quality improvement meetings. Of respondents, 64% were aware of public health agency-based outreach programs and 42% were aware of emergency department BRIDGE programs (Medication Assisted Treatment and immediate referral). Only 9% oversaw naloxone kit distribution (all under the medical director), and 6% had EMS-based outreach programs. In almost all (94%), law enforcement officers carried naloxone and administered it anywhere from a few times a year to greater than 200 in one LEMSA.ConclusionThis study represents an important description of EMS medical directors’ approaches to the impact of OUD as well as trends in protocols and interventions to treat and prevent overdoses. Through this study, we can better understand the variable response to patients with OUD across California.

Laws Mandating Coprescription of Naloxone and Their Impact on Naloxone Prescription in Five US States, 2014-2018.

Objectives. To examine early impacts of laws that require naloxone to be prescribed to patients at increased overdose risk.Methods. Using data from 2014 to 2018 from a large pharmacy chain, CVS Pharmacy, we examined the effects of naloxone-prescribing mandates 90 days before and after they took effect in Arizona, Florida, Rhode Island, Vermont, and Virginia. We compared the number of naloxone doses initiated directly by prescribers and by pharmacy standing order, prescriber specialty, pharmacies dispensing, and payor type by applying linear models and the χ2 test.Results. Naloxone-prescribing mandates increased pharmacy naloxone provision 255% from 90 days before to after implementation. This approach appeared to engage more prescribers (1028 before to 4285 after), complement ongoing naloxone provision under pharmacy standing orders, expand geographic reach (from 40% to 80% of pharmacies dispensing), and broaden the naloxone payor mix in 4 (P < .05) of 5 states.Conclusions. Mandating the prescribing of naloxone quickly expands access to this life-saving medication for more people in more places. Other states should consider mandating the coprescription of naloxone to individuals at increased risk of overdose.

Is Naloxone use in Southeast Alabama Rising? Evaluation of Naloxone Administration in an Emergency Department Setting

BackgroundFatalities caused by drug‐overdose have increased greatly in recent years across the US and is now the leading cause of injury‐related death in the United States. Drug related deaths with cointoxicants are being seen far too often and the increase in prevalence of opioid overdoses with possible concomitant medication use is a public health concern that needs to be addressed. Naloxone (Narcan ®) is an opioid antagonist approved in November 2015 by the FDA to help combat the effects of opioid overdose. Awareness of naloxone’s availability over the counter and education on opioid related overdoses for communities in the United States has been shown to improve opioid overdose deaths. In this study, we document naloxone administration in the Southeast Health Emergency Department to help identify high risk sub‐populations in this region that present with signs of potential opioid overdose and the connection between overdoses for opioids or a cointoxicant.Study DesignA retrospective study was conducted evaluating the administration of naloxone in individuals arriving in the emergency department at Southeast Health from August 01, 2011 to August 31, 2018. Patient cases were collected based on time, route, and dose of naloxone given, and data was then selected based on ICD 10 codes and documented positive reaction to naloxone. Patients who were not between ages 18–89 or were incarcerated or pregnant prior to their hospital were excluded from this study. Further data was collected on patients’ socioeconomic status, medical history, and the course of their encounter.ResultsOf the 721 charts reviewed, 261 were deemed true overdoses and 51 were possible overdoses. While there were more overdoses in individuals with a history of chronic pain or mental illness, this was not statistically significant. The data showed most patients who overdosed were taking both opioids and benzodiazepines.ConclusionsIt is apparent that disabled/retired females over 65 with Medicare or Medicaid were the most likely to be a true opioid overdose.Due to the patient’s mental status upon arrival, not all charts had complete histories or medication records. There were no clear documentation standards, so this varied from by provider and year, making it difficult to determine if there was a true overdose. Data was also dependent on patient honesty, relying on them to admit a history of abuse or what substances they had taken. The number of cases of overdose is likely under reported. Southeast Health is not the only hospital in the area. Emergency responders or home naloxone may have been administered decreasing the number of emergency consults. When considering patients insurance status, only the primary insurance listed was recorded. A patient could have also had a Medicaid plan indicating low income, but this was not noted.Age DistributionFigure 1Naloxone and Past Medical HistoryFigure 2

Effects of Aerosolized Carfentanil on Cardiac Function in Ferrets

Carfentanil (CRF) is a potent synthetic opioid primarily used in anaesthetizing large animals. Exposure to CRF can cause both respiratory and central nervous system depression. Respiratory depression can lead to hypoxia, which may lead to cardiac damage and ultimately death. Myocardial damage has been observed in ferrets exposed to aerosolized CRF. Troponin is a protein complex that plays an integral part in muscle contractions within the myocardium and is used as an indicator of myocardial damage. An increase in blood levels of troponin in exposed ferrets would suggest underlying cardiac damage. Select animals were treated with naloxone (NX), an opioid antagonist, to investigate whether reversing opioid effects altered cardiac function or troponin levels.Male telemetrized ferrets were exposed to aerosolized CRF in a whole‐body plethysmography chamber. Cardiac parameters and respiratory dynamics were collected before, during, and after CRF exposure. Ferrets received no treatment, an oral or intramuscular (i.m.) dose of NX (0.375, 0.75, 1.5, or 3 mg/mL), or water 30 minutes post‐exposure. Euthanasia occurred 24 hours post‐exposure, and blood was collected via descending aorta or heart stick. Serum was separated from blood and analyzed using a high sensitivity rat cardiac troponin‐I enzyme‐linked immunosorbent assay (ELISA).Average troponin levels for all animals ranged from 0.00 – 6.30 ng/mL. Troponin levels were not statistically different across treatment groups, though we observed an increase in mean arterial pressure (MAP) and increased incidents of premature junction complexes for animals exposed to CRF, indicating potential cardiac distress. The increase in MAP could be a compensatory mechanism to overcome hypoxia due to decreased respiration induced by CRF. Both control and exposed animals showed an increase in MAP following treatment; however, sham‐exposed animals had no rise in MAP post‐treatment. This rise in MAP could be due to a combination of NX treatment and a response to being handled for the injection. Overall, our results suggest that CRF does not directly cause myocardial damage, nor do surgically implanted cardiac telemetry devices cause an explicit, permanent increase in troponin levels. Further investigation is needed to determine if cardiac abnormalities observed in ferrets are caused via hypoxia or other unknown mechanisms.Support or Funding InformationOpinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the US Army. This research complied with the Animal Welfare Act and implementing Animal Welfare Regulations and adhered to the principles noted in The Guide for the Care and Use of Laboratory Animals. This research was supported by DTRA RD‐CB. E.P., W.Y.T., M.R. S.P., A.D., and V.D.C. were supported in part by an appointment to the Postgraduate Research Participation Program at the US Army Medical Research Institute of Chemical Defense administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and USAMRDC.

A descriptive study of racial and ethnic differences of drug overdoses and naloxone administration in Pennsylvania

IntroductionDrug overdose is a significant public health problem, yet little is known about racial/ethnic differences in drug overdose rates and/or in responses to a drug overdose following naloxone administration. This paper examines differences in rates of survivorship, response, revival and administration of naloxone by race and ethnicity among those who experienced a drug overdose in Pennsylvania between January 1, 2018 and December 31, 2019. Spatio-temporal variations in drug overdose locations were examined to facilitate understanding of service development, planning, and delivery of effective treatment need. MethodsTen thousand two hundred and ninety drug overdose incidents were analyzed from the Pennsylvania Overdose Information Network (ODIN). The ODIN is a centralized repository that contains information on drug overdoses victims including age, gender and race/ethnicity, naloxone administrations and survivorship, drug(s) suspected of causing the overdose, victim outcomes (e.g. hospitalizations and arrests) and average naloxone dosage per victim. Between group differences were tested using χ2 -tests of independence. Multivariate logistic regression was used to estimate the predicted probability of survivorship according to victim characteristics. All statistical analyses and mapping were performed using the R statistical programming environment. ResultsAbout eighty-seven percent of drug overdose response victims were white, and seventy-one percent were between the ages of 20–39. White females were more likely to receive an overdose response compared to black or Hispanic females. A non-opioid was indicated more frequently in overdoses involving black victims compared to either whites or Latinos. Latinos and blacks were more likely to survive a drug overdose. However, following naloxone administration, no racial or ethnic differences in survivorship were noted. Differences in responsiveness to naloxone and transitions to care following the drug overdose event were also found. Finally, overdoses among Blacks and Latinos demonstrated a stronger spatial patterning across counties compared to whites. ConclusionsThis study found a significant, disparate impact of race/ethnicity on fatal drug overdoses when naloxone is not administered. Further, individuals who were administered naloxone and subsequently received medical care in a hospital experienced lower drug-related mortality, suggesting that first responders are critical intervention points for individuals in need of medical treatment following a drug overdose. However, while naloxone administration is a necessary first step in the recovery process, longitudinal pathways towards treatment are critical to stem the drug overdose crisis.

The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys.

Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [11C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids.