Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Intranasal naloxone (Narcan) for the treatment of heroin and other opiate overdoses - abstracted references:

(1999) NIOSH Alert: Preventing needlestick injuries in health care settings. National Institute for Occupational Safety and Health Volume,  DOI:

Akers, J. L., R. N. Hansen, et al. (2017). "Implementing take-home naloxone in an urban community pharmacy." J Am Pharm Assoc (2003) 57(2S): S161-S167.

                OBJECTIVE: Morbidity and mortality associated with opioid use have increased across the nation, growing into what can only be described as an epidemic. SETTING: In Washington State between 2002 and 2004, the statewide death rate attributed to any opioid was 6.6 per 100,000 people, but between 2011 and 2013 it increased to 8.6 per 100,000 people. Pharmacies provide a unique access point for harm reduction services to patients due to their ease of accessibility in the community. PRACTICE DESCRIPTION: In development of a take-home naloxone (THN) program, there were multiple areas that needed to be considered. These included product selection, collaborative practice agreements, training format and materials, managing patient and provider expectations, partnerships, and community perception of the service. PRACTICE INNOVATION: Initial demographics from our experience of people obtaining THN showed a significant difference in the median age from other available programs in the area (57 years vs. 34, 35, and 31). These people tended to be bystanders, instead of end users of opioids, which led to redirecting marketing of our program. We provided community and group trainings for various organizations around the greater Seattle area. We have trained approximately 1400 unique individuals on how to recognize and respond to an opioid overdose, and how to administer naloxone. EVALUATION: One organization reports 20 successful overdose rescues from 99 kits (100% intranasal route) dispensed by our pharmacy (20.2% rescue rate). RESULTS: Since 2012 when our THN program began, we have seen growth of these programs across the state. Based on data through 2015, deaths from heroin in King County have decreased for the first time in the last 7 years, and the number of people seeking treatment for heroin addiction has increased. CONCLUSION: Take-home naloxone programs can be successfully implemented into community pharmacies to increase access and awareness of opioid overdose recognition and response.

Avetian, G. K., P. Fiuty, et al. (2018). "Use of naloxone nasal spray 4 mg in the community setting: a survey of use by community organizations." Curr Med Res Opin 34(4): 573-576

OBJECTIVE: Naloxone hydrochloride, an opioid antagonist, has been approved as a concentrated 4 mg dose intranasal formulation for the emergency treatment of known or suspected opioid overdose. This new formulation is easier to use and contains a higher dose of naloxone compared with earlier, unapproved kits. A survey of first responders and community-based organizations was conducted to understand initial real-world experiences with this new formulation for opioid overdose reversal. METHODS: In August 2016, 152 US organizations known to have received units of the approved 4 mg dose/unit naloxone nasal spray (Narcan((R))(1) nasal spray 4 mg; NNS) were surveyed regarding experiences using this formulation and availability of recorded data on these cases. Descriptive statistics were calculated based on the number of responses received for each item. RESULTS: Eight first-responder or community-based organizations provided case report data on 261 attempted overdose reversals using NNS, with survival reported for 245 cases. Successful overdose reversals were reported in 98.8% (242/245) of cases; most cases (73.5%; 125/170) reported a time to response of </=5 minutes after NNS administration. Heroin was the substance reportedly involved in a majority (95.4%; 165/173) of these cases; fentanyl was reported to be involved in 5.2% (9/173) of the cases. Many reversals (97.6%; 248/254) involved administration of </=2 units of NNS. Three deaths were reported (NNS was reported to have been administered too late for two cases [the individuals were deceased prior to NNS administration]; details were not provided for the third case). The most commonly reported observed events were "withdrawal" (14.3%; 28/196); "nausea", "vomiting", or "gagging/retching" (10.2%; 20/196); and "irritability" or "anger" (8.7%; 17/196). CONCLUSION: This survey of data provided by first-responder and community-based organizations indicated that NNS was successful at reversing the effects of opioid overdose in most reported cases.

Baca, C. T. and K. J. Grant (2005). "Take-home naloxone to reduce heroin death." Addiction 100(12): 1823-31.

            BACKGROUND: This paper reviews the relevant literature related to the distribution of take-home naloxone. METHODS: A Medline search was conducted on articles published between January 1990 and June 2004 to identify scientific literature relevant to this subject. Those publications were reviewed, and from them other literature was identified and reviewed. RESULTS: The prevalence, pathophysiology and circumstances of heroin overdose, and also bystander response are included in this review. Naloxone peer distribution has been instituted to varying degrees in the United States, Italy, Spain, Germany and the United Kingdom. CONCLUSION: At this point the evidence supporting naloxone distribution is primarily anecdotal, although promising. Although the distribution of naloxone holds promise for further reducing heroin overdose mortality, problems remain. Naloxone alone may be insufficient in some cases to revive the victim, and cardiopulmonary resuscitation (CPR), especially rescue breathing, may also be needed. A second dose of naloxone might be necessary. Complications following resuscitation from overdose may infrequently need in-hospital care. Mortality from injecting without anyone else present will be unaffected by take-home naloxone. Take-home naloxone should be studied in a rigorous scientific manner.

Bailey, A. M. and D. P. Wermeling (2014). "Naloxone for Opioid Overdose Prevention: Pharmacists' Role in Community-Based Practice Settings." Ann Pharmacother.

BACKGROUND: Deaths related to opioid overdose have increased in the past decade. Community-based pharmacy practitioners have worked toward overcoming logistic and cultural barriers to make naloxone distribution for overdose prevention a standard and accepted practice. OBJECTIVE: To describe outpatient naloxone dispensing practices, including methods by which practitioners implement dispensing programs, prescribing patterns that include targeted patient populations, barriers to successful implementation, and methods for patient education. METHODS: Interviews were conducted with providers to obtain insight into the practice of dispensing naloxone. Practitioners were based in community pharmacies or clinics in large metropolitan cities across the country. RESULTS: It was found that 33% of participating pharmacists practice in a community-pharmacy setting, and 67% practice within an outpatient clinic-based location. Dispensing naloxone begins by identifying patient groups that would benefit from access to the antidote. These include licit users of high-dose prescription opioids (50%) or injection drug users and abusers of prescription medications (83%). Patients were identified through prescription records or provider screening tools. Dispensing naloxone required a provider's prescription in 5 of the 6 locations identified. Only 1 pharmacy was able to exercise pharmacist prescriptive authority within their practice. CONCLUSION: Outpatient administration of intramuscular and intranasal naloxone represents a means of preventing opioid-related deaths. Pharmacists can play a vital role in contacting providers, provision of products, education of patients and providers, and dissemination of information throughout the community. Preventing opioid overdose-related deaths should become a major focus of the pharmacy profession.

Baker, J. L., G. D. Kelen, et al. (1987). "Unsuspected human immunodeficiency virus in critically ill emergency patients." Jama 257(19): 2609-11.

Bakhireva, L. N., A. Bautista, et al. (2018). "Barriers and facilitators to dispensing of intranasal naloxone by pharmacists." Subst Abus 39(3): 331-341.

BACKGROUND: Although misuse of prescription opioids has reached epidemic proportions, pharmacy-based preventive services to combat this epidemic are limited. The aims of this study were to identify barriers and facilitators to the dispensing of intranasal naloxone (INN) by pharmacists in New Mexico. METHODS: For this mixed-methods study, a qualitative component (focus group) informed the development of a quantitative component (electronic survey) distributed to all pharmacists registered with the New Mexico Board of Pharmacy and practicing in the state. A 46-item survey included questions about pharmacists' concerns regarding dispensing INN, barriers and facilitators to dispensing INN, efforts needed to increase availability and utilization of pharmacist-dispensed INN, and characteristics of respondents and their pharmacies. RESULTS: Pharmacists from all geographical regions and all types of pharmacy settings were represented in the sample (final N = 390, participation rate 23.5%, including a subset of 182 community pharmacists). The main barriers identified were (1) out-of-pocket costs for patients; (2) time constraints for pharmacists; and (3) inadequate reimbursement for pharmacists. The main facilitators were (1) increased awareness among opioid-using patients and family members about the need for INN; (2) additional education to the general public; and (3) additional training for pharmacists on how to initiate discussions about INN with high-risk patients. Some community pharmacists were concerned that INN dispensing would promote opioid abuse (16.5%) and attract undesirable clientele (14.3%). In a multivariable logistic regression analysis of a community pharmacy subset, a higher number of concerns about INN (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.82-0.93) and a pharmacy setting in a chain grocery or a "big box" store (OR = 0.38; 95% CI: 0.16-0.92) were associated with decreased odds of dispensing INN. CONCLUSIONS: Effective intervention strategies for increasing dispensing of intranasal naloxone by pharmacists should focus on pharmacists' concerns, include education to multiple audiences, and address provider-level, system-level, and society-level barriers.

Barry, T., J. Klimas, et al. (2017). "Opiate addiction and overdose: experiences, attitudes, and appetite for community naloxone provision." Br J Gen Pract 67(657): e267-e273.

                BACKGROUND: More than 200 opiate overdose deaths occur annually in Ireland. Overdose prevention and management, including naloxone prescription, should be a priority for healthcare services. Naloxone is an effective overdose treatment and is now being considered for wider lay use. AIM: To establish GPs' views and experiences of opiate addiction, overdose care, and naloxone provision. DESIGN AND SETTING: An anonymous postal survey to GPs affiliated with the Department of Academic General Practice, University College Dublin, Ireland. METHOD: A total of 714 GPs were invited to complete an anonymous postal survey. Results were compared with a parallel GP trainee survey. RESULTS: A total of 448/714 (62.7%) GPs responded. Approximately one-third of GPs were based in urban, rural, and mixed areas. Over 75% of GPs who responded had patients who used illicit opiates, and 25% prescribed methadone. Two-thirds of GPs were in favour of increased naloxone availability in the community; almost one-third would take part in such a scheme. A higher proportion of GP trainees had used naloxone to treat opiate overdose than qualified GPs. In addition, a higher proportion of GP trainees were willing to be involved in naloxone distribution than qualified GPs. Intranasal naloxone was much preferred to single (P<0.001) or multiple dose (P<0.001) intramuscular naloxone. Few GPs objected to wider naloxone availability, with 66.1% (n = 292) being in favour. CONCLUSION: GPs report extensive contact with people who have opiate use disorders but provide limited opiate agonist treatment. They support wider availability of naloxone and would participate in its expansion. Development and evaluation of an implementation strategy to support GP-based distribution is urgently needed.

Barton, Ed, et al. (2005). "Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting." J Emerg Med 29(3): 265-71.

            Prehospital providers are at increased risk for blood-borne exposure and disease due to the nature of their environment. The use if intranasal (i.n.) medications in high-risk populations may limit this risk of exposure. To determine the efficacy of i.n. naloxone in the treatment of suspected opiate overdose patients in the prehospital setting, a prospective, nonrandomized trial of administering i.n. naloxone by paramedics to patients with suspected opiate overdoses over a 6-month period was performed. All adult patients encountered in the prehospital setting as suspected opiate overdose (OD), found down (FD), or with altered mental status (AMS) who met the criteria for naloxone administration were included in the study. i.n. naloxone (2 mg) was administered immediately upon patient contact and before i.v. insertion and administration of i.v. naloxone (2 mg). Patients were then treated by EMS protocol. The main outcome measures were: time of i.n. naloxone administration, time of i.v. naloxone administration, time of appropriate patient response as reported by paramedics. Ninety-five patients received i.n. naloxone and were included in the study. A total of 52 patients responded to naloxone by either i.n. or i.v., with 43 (83%) responding to i.n. naloxone alone. Seven patients (16%) in this group required further doses of i.v. naloxone. In conclusion, i.n. naloxone is a novel alternative method for drug administration in high-risk patients in the prehospital setting with good overall effectiveness. The use of this route is further discussed in relation to efficacy of treatment and minimizing the risk of blood-borne exposures to EMS personnel.

Behar, E., G. M. Santos, et al. (2015). "Brief overdose education is sufficient for naloxone distribution to opioid users." Drug Alcohol Depend 148: 209-212.

BACKGROUND: While drug users are frequently equipped with naloxone for lay opioid overdose reversal, the amount of education needed to ensure knowledge of indications and administration is unknown. METHODS: We administered four instruments, assessing comfort and knowledge around opioid overdose and naloxone administration, to opioid users receiving naloxone for the first time (N=60) and upon returning for a refill (N=54) at community distribution programs. Participants completed the instruments prior to receiving naloxone; first-time recipients repeated the instruments immediately after the standardized 5-10min education. RESULTS: Comfort with recognition of, response to, and administration of naloxone for an overdose event significantly increased after brief education among first-time recipients (p<0.05). Knowledge of appropriate responses to opioid overdose was high across all assessments; 96% of participants could identify at least one acceptable action to assess and one acceptable action to care for an opioid overdose. Facility with naloxone administration was high across all assessments and significantly increased for intranasal administration after education for first-time recipients (p<0.001). First-time recipients (before and after education) and refillers demonstrated a high level of knowledge on the Brief Overdose Recognition and Response Assessment, correctly identifying a mean of 13.7 out of 16 overdose scenarios. CONCLUSIONS: Opioid users seeking naloxone in San Francisco have a high level of baseline knowledge around recognizing and responding to opioid overdose and those returning for refills retain that knowledge. Brief education is sufficient to improve comfort and facility in recognizing and managing overdose.

Belz, D., J. Lieb, et al. (2006). "Naloxone use in a tiered-response emergency medical services system." Prehosp Emerg Care 10(4): 468-71.

            OBJECTIVE: To examine the delivery and effect of naloxone for opioid overdose in a tiered-response emergency medical services (EMS) system and to ascertain how much time could be saved if the first arriving emergency medical technicians (EMTs) could have administered intranasal naloxone. METHODS: This was case series of all EMS-treated overdose patients who received naloxone by paramedics in a two-tiered EMS system during 2004. The system dispatches basic life support-trained fire fighter-EMTs and/or advanced life support-trained paramedics depending on the severity of cases. Main outcomes were geographic distribution of naloxone-treated overdose, severity of cases, response to naloxone, and time interval between arrival of EMTs and arrival of paramedics at the scene. RESULTS: There were 164 patients who received naloxone for suspected overdose. There were 75 patients (46%) initially unresponsive to painful stimulus. Respiratory rate was <10 breaths/min in 79 (48%). Death occurred in 36 (22%) at the scene or during transport. A full or partial response to naloxone occurred in 119 (73%). Recognized adverse reactions were limited to agitation/combativeness in 25 (15%) and emesis in six (4%). Average EMT arrival time was 5.9 minutes. Average paramedic arrival time was 11.6 minutes in most cases and 16.1 minutes in 46 cases (28%) in which paramedics were requested by EMTs at the scene. CONCLUSIONS: There is potential for significantly earlier delivery of naloxone to patients in opioid overdose if EMTs could deliver intranasal naloxone. A pilot study training and authorizing EMTs to administer intranasal naloxone in suspected opioid overdose is warranted.

Chang, G., M. Davids, et al. (2017). "Overdose education and naloxone distribution for veterans with opioid use disorder: Results from a pilot initiative." J Addict Dis 36(4): 217-221.

    Patients with opioid use disorder are at a high risk of overdose. To minimize that risk, a program offering intranasal naloxone rescue kits was piloted at a Veterans Administration Hospital. The purpose of this study was to characterize veterans who accepted these potentially lifesaving kits. Retrospective medical chart review of 158 veterans with opioid use disorder receiving treatment on either the inpatient psychiatry detoxification units or outpatient methadone maintenance setting who were offered overdose education and naloxone rescue kits. One hundred and ten of 158 veterans (70%) accepted overdose education and naloxone rescue. Overall, they had a mean age of 39.1 years and averaged 12.7 years of opioid use. In the prior month, they averaged 14.3 days of heroin use; they used alone 48.5% of the time. They estimated an average of 2.8 accidental overdoses over their lifetimes. There were few significant differences between those who accepted and those who declined with regard to demographic and clinical variables. However, significantly higher percentages of outpatients accepted overdose education and naloxone rescue compared to inpatients (89% versus 63%, p = 0.003, Chi-square); the odds of acceptance were increased four-fold when offered to outpatients. Outpatients were nearly a decade older, with more years of opioid use (19.0 versus 11.0), but with less utilization of inpatient services in the prior year (all p < 0.05). The main finding was that 70% of veterans accepted overdose education and naloxone rescue, but significantly higher proportions of outpatients were more receptive than inpatients (89% versus 63%, p = 0.003). Efforts to increase overdose education and naloxone rescue acceptance in all settings are encouraged.

Coffin, P. O. and S. D. Sullivan (2013). "Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal." Ann Intern Med 158(1): 1-9.

BACKGROUND: Opioid overdose is a leading cause of accidental death in the United States. OBJECTIVE: To estimate the cost-effectiveness of distributing naloxone, an opioid antagonist, to heroin users for use at witnessed overdoses. DESIGN: Integrated Markov and decision analytic model using deterministic and probabilistic analyses and incorporating recurrent overdoses and a secondary analysis assuming heroin users are a net cost to society. DATA SOURCES: Published literature calibrated to epidemiologic data. TARGET POPULATION: Hypothetical 21-year-old novice U.S. heroin user and more experienced users with scenario analyses. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Naloxone distribution for lay administration. OUTCOME MEASURES: Overdose deaths prevented and incremental cost-effectiveness ratio (ICER). RESULTS OF BASE-CASE ANALYSIS: In the probabilistic analysis, 6% of overdose deaths were prevented with naloxone distribution; 1 death was prevented for every 227 naloxone kits distributed (95% CI, 71 to 716). Naloxone distribution increased costs by $53 (CI, $3 to $156) and quality-adjusted life-years by 0.119 (CI, 0.017 to 0.378) for an ICER of $438 (CI, $48 to $1706). RESULTS OF SENSITIVITY ANALYSIS: Naloxone distribution was cost-effective in all deterministic and probabilistic sensitivity and scenario analyses, and it was cost-saving if it resulted in fewer overdoses or emergency medical service activations. In a "worst-case scenario" where overdose was rarely witnessed and naloxone was rarely used, minimally effective, and expensive, the ICER was $14 000. If national drug-related expenditures were applied to heroin users, the ICER was $2429. LIMITATION: Limited sources of controlled data resulted in wide CIs. CONCLUSION: Naloxone distribution to heroin users is likely to reduce overdose deaths and is cost-effective, even under markedly conservative assumptions. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Coffin, P., J. Rich, et al. (2016). "While we dither, people continue to die from overdose: Comments on 'Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?'." Addiction 111(10): 1880-1881.

Compton, W. M., N. D. Volkow, et al. (2013). "Expanded access to opioid overdose intervention: research, practice, and policy needs." Ann Intern Med 158(1): 65-66.

Davis, C. S., S. Ruiz, et al. (2014). "Expanded access to naloxone among firefighters, police officers, and emergency medical technicians in Massachusetts." Am J Public Health 104(8): e7-9.

Naloxone is a medication that reverses respiratory depression from opioid overdose if given in time. Paramedics routinely administer naloxone to opioid overdose victims in the prehospital setting, and many states are moving to increase access to the medication. Several jurisdictions have expanded naloxone administration authority to nonparamedic first responders, and others are considering that step. We report here on policy change in Massachusetts, where several communities have equipped emergency medical technicians, law enforcement officers, and firefighters with naloxone.

Dahlem, C. H., M. J. Horstman, et al. (2015). "Development and implementation of intranasal naloxone opioid overdose response protocol at a homeless health clinic." J Am Assoc Nurse Pract.

                PURPOSE: To describe the development, implementation, and preliminary evaluation of Opioid Overdose Response Protocol using intranasal (IN) naloxone in a homeless shelter. DATA SOURCES: Opioid Overdose Response Protocol and training curriculum were developed using the Massachusetts Department of Public Health Opioid Overdose Education and Naloxone Distribution (OEND) flow chart, the American Heart Association (AHA) simplified adult basic life support algorithm, and resources through Harms Reduction Coalition. CONCLUSIONS: Intranasal naloxone offers a safe and effective method for opioid reversal. To combat the rising incidence of opioid overdose, IN naloxone should be made available at homeless shelters and other facilities with high frequency of opioid overdose, including the training of appropriate staff. This project has demonstrated the effective training and implementation of an Opioid Overdose Response Protocol, based on feedback received from cardiopulmonary resuscitation (CPR) trained nonhealthcare staff. Nurse practitioners (NPs), with our focus on patient care, prevention, and education, are well suited to the deployment of this life-saving protocol. IMPLICATIONS FOR PRACTICE: NPs are in critical positions to integrate opioid overdose prevention education and provide naloxone rescue kits in clinical practices.

Dietze, P., M. Jauncey, et al. (2019). "Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial." JAMA Netw Open 2(11): e1914977.

Importance: Previous unblinded clinical trials suggested that the intranasal route of naloxone hydrochloride was inferior to the widely used intramuscular route for the reversal of opioid overdose. Objective: To test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose. Design, Setting, and Participants: A double-blind, double-dummy randomized clinical trial was conducted at the Uniting Medically Supervised Injecting Centre in Sydney, Australia. Clients of the center were recruited to participate from February 1, 2012, to January 3, 2017. Eligible clients were aged 18 years or older with a history of injecting drug use (n = 197). Intention-to-treat analysis was performed for all participants who received both intranasal and intramuscular modes of treatment (active or placebo). Interventions: Clients were randomized to receive 1 of 2 treatments: (1) intranasal administration of naloxone hydrochloride 800 mug per 1 mL and intramuscular administration of placebo 1 mL or (2) intramuscular administration of naloxone hydrochloride 800 mug per 1 mL and intranasal administration of placebo 1 mL. Main Outcomes and Measures: The primary outcome measure was the need for a rescue dose of intramuscular naloxone hydrochloride (800 mug) 10 minutes after the initial treatment. Secondary outcome measures included time to adequate respiratory rate greater than or equal to 10 breaths per minute and time to Glasgow Coma Scale score greater than or equal to 13. Results: A total of 197 clients (173 [87.8%] male; mean [SD] age, 34.0 [7.82] years) completed the trial, of whom 93 (47.2%) were randomized to intramuscular naloxone dose and 104 (52.8%) to intranasal naloxone dose. Clients randomized to intramuscular naloxone administration were less likely to require a rescue dose of naloxone compared with clients randomized to intranasal naloxone administration (8 [8.6%] vs 24 [23.1%]; odds ratio, 0.35; 95% CI, 0.15-0.66; P = .002). A 65% increase in hazard (hazard ratio, 1.65; 95% CI, 1.21-2.25; P = .002) for time to respiratory rate of at least 10 and an 81% increase in hazard (hazard ratio, 1.81; 95% CI, 1.28-2.56; P = .001) for time to Glasgow Coma Scale score of at least 13 were observed for the group receiving intranasal naloxone compared with the group receiving intramuscular naloxone. No major adverse events were reported for either group. Conclusions and Relevance: This trial showed that intranasally administered naloxone in a supervised injecting facility can reverse opioid overdose but not as efficiently as intramuscularly administered naloxone can, findings that largely replicate those of previous unblinded clinical trials. These results suggest that determining the optimal dose and concentration of intranasal naloxone to respond to opioid overdose in real-world conditions is an international priority. Trial Registration: Identifier: ACTRN12611000852954.

Doe-Simkins, M., A. Y. Walley, et al. (2009). "Saved by the nose: bystander-administered intranasal naloxone hydrochloride for opioid overdose." Am J Public Health 99(5): 788-91.

            Administering naloxone hydrochloride (naloxone) during an opioid overdose reverses the overdose and can prevent death. Although typically delivered via intramuscular or intravenous injection, naloxone may be delivered via intranasal spray device. In August 2006, the Boston Public Health Commission passed a public health regulation that authorized an opioid overdose prevention program that included intranasal naloxone education and distribution of the spray to potential bystanders. Participants were taught by trained nonmedical needle exchange staff. After 15 months, the program provided training and intranasal naloxone to 385 participants who reported 74 successful overdose reversals. Problems with intranasal naloxone were uncommon. Overdose prevention education with distribution of intranasal naloxone is a feasible public health intervention to address opioid overdose.

Doe-Simkins, M., E. Quinn, et al. (2014). "Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study." BMC Public Health 14: 297.

BACKGROUND: One approach to preventing opioid overdose, a leading cause of premature, preventable mortality, is to provide overdose education and naloxone distribution (OEND). Two outstanding issues for OEND implementation include 1) the dissemination of OEND training from trained to untrained community members; and 2) the concern that OEND provides active substance users with a false sense of security resulting in increased opioid use. METHODS: To compare overdose rescue behaviors between trained and untrained rescuers among people reporting naloxone rescue kit use; and determine whether heroin use changed after OEND, we conducted a retrospective cohort study among substance users in the Massachusetts OEND program from 2006 to 2010. We used chi square and t-test statistics to compare the differences in overdose management characteristics among overdoses managed by trained versus untrained participants. We employed Wilcoxon signed rank test to compare median difference among two repeated measures of substance use among participants with drug use information collected more than once. RESULTS: Among 4,926 substance-using participants, 295 trained and 78 untrained participants reported one or more rescues, resulting in 599 rescue reports. We found no statistically significant differences in help-seeking (p = 0.41), rescue breathing (p = 0.54), staying with the victim (p = 0.84) or in the success of naloxone administration (p = 0.69) by trained versus untrained rescuers. We identified 325 OEND participants who had drug use information collected more than once. We found no significant overall change in the number of days using heroin in past 30 days (decreased 38%, increased 35%, did not change 27%, p = 0.52). CONCLUSION: Among 4926 substance users who participated in OEND, 373(7.6%) reported administering naloxone during an overdose rescue. We found few differences in behavior between trained and untrained overdose rescuers. Prospective studies will be needed to determine the optimal level of training and whether naloxone rescue kits can meet an over-the-counter standard. With no clear evidence of increased heroin use, this concern should not impede expansion of OEND programs or policies that support them.

Dunn, K. E., F. S. Barrett, et al. (2018). "Naloxone formulation for overdose reversal preference among patients receiving opioids for pain management." Addict Behav 86: 56-60.

BACKGROUND: Opioid-related overdose has increased 137% in the past decade. Training nonmedical bystanders to administer naloxone (Narcan) is a widely-researched intervention that has been associated with decreases in overdose rates in the communities in which it has been implemented. A recent review advocated for noninjectable formulations of naloxone, however patient preference for naloxone formulations has not yet been examined (Strang et al., 2016). METHODS: Two cohorts of respondents (N1=501, N2=172) who reported currently being prescribed an opioid for pain management were recruited through the crowd-sourcing program Amazon Mechanical Turk (MTurk) to assess their preference for naloxone formulations. All respondents were provided a description of different formulations and asked to indicate all formulations they would be willing to administer for overdose reversal and to then rank formulations in order of preference. RESULTS: Results were remarkably similar across both cohorts. Specifically, respondents preferred noninjectable formulations (intranasal, sublingual, buccal) over injectable (intravenous, intramuscular) formulations. A small percent (8.9%-9.8%) said they would never be willing to administer naloxone. An identical percent of respondents in both cohorts (44.9%) rated intranasal as their most preferred formulation. CONCLUSIONS: Two independent cohorts of respondents who were receiving opioid medications for pain management reported a preference for noninjectable over injectable formulations of naloxone to reverse an opioid overdose. Though initial preference is only one of many factors that impacts ultimate public acceptance and uptake of a new product, these results support the additional research and development of noninjectable naloxone formulations.

Dwyer, K., A. Y. Walley, et al. (2015). "Opioid education and nasal naloxone rescue kits in the emergency department." West J Emerg Med 16(3): 381-384.

                INTRODUCTION: Emergency departments (EDs) may be high-yield venues to address opioid deaths with education on both overdose prevention and appropriate actions in a witnessed overdose. In addition, the ED has the potential to equip patients with nasal naloxone kits as part of this effort. We evaluated the feasibility of an ED-based overdose prevention program and described the overdose risk knowledge, opioid use, overdoses, and overdose responses among participants who received overdose education and naloxone rescue kits (OEN) and participants who received overdose education only (OE). METHODS: Program participants were surveyed by telephone after their ED visit about their substance use, overdose risk knowledge, history of witnessed and personal overdoses, and actions in a witnessed overdose including use of naloxone. RESULTS: A total of 415 ED patients received OE or OEN between January 1, 2011 and February 28, 2012. Among those, 51 (12%) completed the survey; 37 (73%) of those received a naloxone kit, and 14 (27%) received OE only. Past 30-day opioid use was reported by 35% OEN and 36% OE, and an overdose was reported by 19% OEN and 29% OE. Among 53% (27/51) of participants who witnessed another individual experiencing an overdose, 95% OEN and 88% OE stayed with victim, 74% OEN and 38% OE called 911, 26% OEN and 25% OE performed rescue breathing, and 32% OEN (n=6) used a naloxone kit to reverse the overdose. We did not detect statistically significant differences between OEN and OE-only groups in opioid use, overdose or response to a witnessed overdose. CONCLUSION: This is the first study to demonstrate the feasibility of ED-based opioid overdose prevention education and naloxone distribution to trained laypersons, patients and their social network. The program reached a high-risk population that commonly witnessed overdoses and that called for help and used naloxone, when available, to rescue people. While the study was retrospective with a low response rate, it provides preliminary data for larger, prospective studies of ED-based overdose prevention programs.

Eggleston, W., C. Podolak, et al. (2018). "A randomized usability assessment of simulated naloxone administration by community members." Addiction 113(12): 2300-2304.

BACKGROUND AND AIMS: Expanded access to naloxone has been identified as a key intervention for reducing opioid-related morbidity and mortality. It is not known which naloxone device will result in rapid, successful administration when administered by community members. The aims of this study were to estimate and compare (1) the rate of successful administration and (2) time to successful administration for single-step nasal spray, multi-step atomized nasal spray and intramuscular simulated naloxone by community members. DESIGN: A prospective, single-site, open-label, randomized usability assessment of simulated naloxone administration in a convenience sample of community members. Participants were randomized to single-step nasal spray (SP), multi-step atomized nasal spray (AT) or intramuscular simulated (IM) naloxone and asked to administer the simulated medication to a mannequin after completing a 2-minute training video. SETTING: New York, USA at a state fair that attracts between 60 000 and 120 000 individuals daily. PARTICIPANTS: A total of 138 participants completed the study over a 2-day period in September 2016. All participants were at least 18 years of age and had no prior naloxone training. MEASUREMENTS: The rate of successful administration and time to successful administration were recorded for each device. FINDINGS: The SP device (100%; P < 0.001) had a higher rate of success compared with the IM device (69.6%). Although success differed between the AT (89.1%) device and IM device, as well as the AT device and SP device, these differences were not significant. The SP device also had a shorter median time to successful administration (34.3 sec) compared with the IM (99.9 sec; P < 0.001) and AT (110.3; P < 0.001) devices. CONCLUSIONS: After video training, community members are able to (1) administer single-step nasal spray naloxone with a higher rate of success than intramuscular naloxone in a simulated overdose setting and (2) administer single-step nasal spray naloxone more rapidly than both intramuscular and multi-step atomized nasal spray naloxone.

Fareed, A., A. M. Buchanan-Cummings, et al. (2015). "Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report." Am J Addict 24(5): 388-390.

                BACKGROUND: This is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin. METHODS: The Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. The Atlanta VA Medical Center adopted this program to reduce the risk of opioid overdose in high risk patients. RESULTS: Over the past year, we provided educational sessions for 63 veterans and their families. We also prescribed 41 naloxone kits. We have received three reports of opioid overdose reversal with use of naloxone kits prescribed by the Atlanta VA Medical Center. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The authors recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose death in the United States and worldwide. (Am J Addict 2015;24:388 -390).

Fisher, R., D. O'Donnell, et al. (2016). "Police Officers Can Safely and Effectively Administer Intranasal Naloxone." Prehosp Emerg Care: 1-6.

INTRODUCTION: Opioid overdose rates continue to rise at an alarming rate. One method used to combat this epidemic is the administration of naloxone by law enforcement. Many cities have implemented police naloxone administration programs, but there is a minimal amount of research examining this policy. The following study examines data over 18 months, after implementation of a police naloxone program in an urban setting. We describe the most common indications and outcomes of naloxone administration as well as examine the incidence of arrest, immediate detention, or voluntary transport to the hospital. In doing so, this study seeks to describe the clinical factors surrounding police use of naloxone, and the effects of police administration. METHODS: All police officer administrations were queried from April 2014 through September 2015 (n = 126). For each incident we collected the indication, response, and disposition of the patient that was recorded on a "sick-injured civilian" report that officers were required to complete after administration of naloxone. All of the relevant information was abstracted from this report into an electronic data collection form that was then input into SPSS for analysis. RESULTS: The most common indication for administration was unconscious/unresponsive (n = 117; 92.9%) followed by slowed breathing (n = 72; 57.1%), appeared blue (n = 63; 50.0%) and not breathing (n = 41; 32.5%). After administration of naloxone the majority of patients regained consciousness (n = 82; 65.1%) followed by began to breath (n = 71; 56.3%). However, in 17.5% (n = 22) of the cases "Nothing" happened when naloxone was administered. The majority of patients were transported voluntarily to the hospital (n = 122; 96.8%). Lastly, there was only one report where the patient became combative. CONCLUSION: Our study shows that police officers trained in naloxone administration can correctly recognize symptoms of opioid overdose, and can appropriately administer naloxone without significant adverse effects or outcomes. Furthermore, the administration of police naloxone does not result in a significant incidence of combativeness or need for scene escalations such as immediate detention. Further research is needed to investigate the impact of police naloxone; specifically, comparing outcomes of police delivery to EMS alone, as well as the impact on rural opioid overdoses.

Frauger, E., F. Kheloufi, et al. (2018). "[Interest of take-home naloxone for opioid overdose]." Therapie 73(6): 511-520.

Over the course of these last decades, we observed a change on opioid use with the marketing of opiate maintenance treatment, an increase of opioids used for pain management and recent concerns have arisen around the use of synthetic opioid. The World Health Organization (WHO) reports around 70,000 people opioid overdose death each year. In France, according to the DRAMES program (fatalities in relation with abuse of licit or illicit drugs) of the French addictovigilance network, most of deaths are related to opioids overdose (especially methadone, following by heroin, buprenorphine and opioid used for pain management). Opioid overdose is treatable with naloxone, an opioid antagonist which rapidly reverses the effects of opioids. In recent years, a number of programs around the world have shown that it is feasible to provide naloxone to people likely to witness an opioid overdose. In 2014, the WHO published recommendations for this provision and the need to train users and their entourage in the management of opioid overdose. In this context, in July 2016, French drug agency has granted a temporary authorization for use of a naloxone nasal spray Nalscue((R)). Because different opioids can be used and because each opioid has specific characteristics (pharmacodynamics, pharmacokinetics, galenic form...), the risk of overdose may differ from one opioid to another and it may be necessary, depending on the clinical context, to use larger and repeated doses of naloxone.

Galea, S., N. Worthington, et al. (2006). "Provision of naloxone to injection drug users as an overdose prevention strategy: early evidence from a pilot study in New York City." Addict Behav 31(5): 907-912.

INTRODUCTION: Naloxone, an opiate antagonist that can avert opiate overdose morality, has long been prescribed to drug users in Europe and in a few US cities. However, there has been little documented evidence of naloxone distribution programs and their feasibility in the peer reviewed literature in the US. METHODS: A pilot overdose prevention and reversal program was implemented in a New York City syringe exchange program. We assessed demographics, drug use, and overdose history, experience, and behavior at baseline, when participants returned for prescription refills, and 3 months after baseline assessment. RESULTS: 25 participants were recruited. 22 (88%) participants were successfully followed-up in the first 3 months; of these, 11 (50%) participants reported witnessing a total of 26 overdoses during the follow-up period. Among 17 most-recent overdoses witnessed, naloxone was administered 10 times; all persons who had naloxone administered lived. DISCUSSION: Naloxone administration by injection drug users is feasible as part of a comprehensive overdose prevention strategy and may be a practicable way to reduce overdose deaths on a larger scale.

Green, T. C., M. Ray, et al. (2014). "Two cases of intranasal naloxone self-administration in opioid overdose." Subst Abus 35(2): 129-132.

ABSTRACT. Background: Overdose is a leading cause of death for former prisoners, exacting its greatest toll during the first 2 weeks post release. Protective effects have been observed with training individuals at high risk of overdose and prescribing them naloxone, an opioid antagonist that reverses the effects of the opioid-induced respiratory depression that causes death. Cases: The authors report 2 people with opiate use histories who self-administered intranasal naloxone to treat their own heroin overdoses following release from prison. Patient A is a 34-year-old male, who reported having experienced an overdose on heroin the day after he was released from incarceration. Patient B is a 29-year-old female, who reported an overdose on her first injection of heroin, 17 days post release from incarceration. Both patients self-administered the medication but were assisted at some point during the injury by a witness whom they had personally instructed in how to prepare and administer the medication. Neither patient experienced withdrawal symptoms following exposure to naloxone. Discussion: Self-administration of naloxone should not be a goal of overdose death prevention training. A safer, more reliable approach is to prescribe naloxone to at-risk patients and train and also equip members of their household and social or drug-using networks in overdose prevention and response.

Guadamuz, J. S., G. C. Alexander, et al. (2019). "Availability and Cost of Naloxone Nasal Spray at Pharmacies in Philadelphia, Pennsylvania, 2017." JAMA Netw Open 2(6): e195388

Importance: Despite the increasingly important role of pharmacies in the implementation of naloxone access laws, there is limited information on the impact of such laws at the local level. Objective: To evaluate the availability (with or without a prescription) and cost of naloxone nasal spray at pharmacies in Philadelphia, Pennsylvania, following a statewide standing order enacted in Pennsylvania in August 2015 to allow pharmacies to dispense naloxone without a prescription. Design, Setting, and Participants: A survey study was conducted by telephone of all pharmacies in Philadelphia between February and August 2017. Pharmacies were geocoded and linked with the American Community Survey (2011-2015) to obtain information on the demographic characteristics of census tracts and the Medical Examiner's Office of the Philadelphia Department of Public Health to derive information on the number of opioid overdose deaths per 100000 people for each planning district. Data were analyzed from March 2018 to February 2019. Main Outcomes and Measures: Availability and out-of-pocket cost of naloxone nasal spray (with or without a prescription) at Philadelphia pharmacies overall and by pharmacy and neighborhood characteristics. Results: Of 454 eligible pharmacies, 418 were surveyed (92.1% response rate). One in 3 pharmacies (34.2%) had naloxone nasal spray in stock; of these, 61.5% indicated it was available without a prescription. There were significant differences in the availability of naloxone by pharmacy type and neighborhood characteristics. Naloxone was both more likely to be in stock (45.9% vs 27.8%; difference, 18.0%; 95% CI, 8.3%-27.8%; P < .001) and available without a prescription (80.6% vs 42.2%; difference, 38.4%; 95% CI, 23.0%-53.8%; P < .001) in chain stores than in independent stores. Naloxone was also less likely to be available in planning districts with very elevated rates of opioid overdose death (>/=50 per 100000 people) compared with those with lower rates (31.1% vs 38.5%). The median (interquartile range) out-of-pocket cost among pharmacies offering naloxone without a prescription was $145 ($119-$150); costs were greatest in independent pharmacies and planning districts with elevated rates of opioid overdose death. Conclusions and Relevance: Despite the implementation of a statewide standing order in Pennsylvania more than 3 years prior to this study, only one-third of Philadelphia pharmacies carried naloxone nasal spray and many also required a physician's prescription. Efforts to strengthen the implementation of naloxone access laws and better ensure naloxone supply at local pharmacies are warranted, especially in localities with the highest rates of overdose death.

Gulec, N., J. Lahey, et al. (2017). "Basic and Advanced EMS Providers Are Equally Effective in Naloxone Administration for Opioid Overdose in Northern New England." Prehosp Emerg Care: 1-7.

Gulec, N., J. Lahey, et al. (2018). "Basic and Advanced EMS Providers Are Equally Effective in Naloxone Administration for Opioid Overdose in Northern New England." Prehosp Emerg Care 22(2): 163-169.

                OBJECTIVE: Overdose mortality from illicit and prescription opioids has reached epidemic proportions in the United States, especially in rural areas. Naloxone is a safe and effective agent that has been shown to successfully reverse the effects of opioid overdose in the prehospital setting. The National EMS Scope of Practice Model currently only recommends advanced life support (ALS) providers to administer naloxone; however, some individual states have expanded this scope of practice to include intranasal (IN) administration of naloxone by basic life support (BLS) providers, including the Northern New England states. This study compares the effectiveness and appropriateness of naloxone administration between BLS and ALS providers. METHODS: All Vermont, New Hampshire, and Maine EMS patient encounters between April 1, 2014 and December 31, 2016 where naloxone was administered were examined and 3,219 patients were identified. The proportion of successful reversals of opioid overdose, based on improvement in the Glasgow Coma Scale (GCS), respiratory rate (RR), and provider global assessment (GA) of response to medication was compared between BLS and ALS providers using a Chi-Squared statistic, Fisher's exact or Wilcoxon rank-sum test. RESULTS: There was no significant difference in the percent improvement in GCS between BLS and ALS (64% and 64% P = 0.94). There was no significant difference in the percentage of improvement in RR between BLS and ALS (45% and 48% P = 0.43). There was a significant difference in the percentage of improvement of GA between BLS and ALS (80% and 67% P < 0.001). There was no significant difference in determining appropriate cases to administer naloxone where RR < 12 and GCS < 15 between BLS and ALS (42% and 43% P = 0.94). CONCLUSIONS: BLS providers were as effective as ALS providers in improving patient outcome measures after naloxone administration and in identifying patients for whom administration of naloxone is appropriate. These findings support expanding the National EMS Scope of Practice Model to include BLS administration of intranasal naloxone for suspected opioid overdoses.

Hammett, T. M., S. Phan, et al. (2014). "Pharmacies as providers of expanded health services for people who inject drugs: a review of laws, policies, and barriers in six countries." BMC Health Serv Res 14: 261.

BACKGROUND: People who inject drugs (PWID) are underserved by health providers but pharmacies may be their most accessible care settings. METHODS: Studies in the U.S., Russia, Vietnam, China, Canada and Mexico employed a three-level (macro-, meso-, and micro-) model to assess feasibility of expanded pharmacy services for PWID. Studies employed qualitative and quantitative interviews, review of legal and policy documents, and information on the knowledge, attitudes, and practices of key stakeholders. RESULTS: Studies produced a mixed assessment of feasibility. Provision of information and referrals by pharmacies is permissible in all study sites and sale and safe disposal of needles/syringes by pharmacies is legal in almost all sites, although needle/syringe sales face challenges related to attitudes and practices of pharmacists, police, and other actors. Pharmacy provision of HIV testing, hepatitis vaccination, opioid substitution treatment, provision of naloxone for drug overdose, and abscess treatment, face more serious legal and policy barriers. DISCUSSION: Challenges to expanded services for drug users in pharmacies exist at all three levels, especially the macro-level characterized by legal barriers and persistent stigmatization of PWID. Where deficiencies in laws, policies, and community attitudes block implementation, stakeholders should advocate for needed legal and policy changes and work to address community stigma and resistance. Laws and policies are only as good as their implementation, so attention is also needed to meso- and micro- levels. Policies, attitudes, and practices of police departments and pharmacy chains as well as knowledge, attitudes, and practices of individual PWID, individual pharmacies, and police officers should support rather than undermine positive laws and expanded services. Despite the challenges, pharmacies remain potentially important venues for delivering health services to PWID.

Heavey, S. C., A. M. Delmerico, et al. (2018). "Descriptive Epidemiology for Community-wide Naloxone Administration by Police Officers and Firefighters Responding to Opioid Overdose." J Community Health 43(2): 304-311.

                Recently implemented New York State policy allows police and fire to administer intranasal naloxone when responding to opioid overdoses. This work describes the geographic distribution of naloxone administration (NlxnA) by police and fire when responding to opioid overdoses in Erie County, NY, an area of approximately 920,000 people including the City of Buffalo. Data are from opioid overdose reports (N = 800) filed with the Erie County Department of Health (July 2014-June 2016) by police/fire and include the overdose ZIP code, reported drug(s) used, and NlxnA. ZIP code data were geocoded and mapped to examine spatial patterns of NlxnA. The highest NlxnA rates (range: 0.01-84.3 per 10,000 population) were concentrated within the city and first-ring suburbs. Within 3 min 27.3% responded to NlxnA and 81.6% survived the overdose. The average individual was male (70.3%) and 31.4 years old (SD = 10.3). Further work is needed to better understand NlxnA and overdose, including exploring how the neighborhood environment creates a context for drug use, and how this context influences naloxone use and overdose experiences.

Han, J. K., L. G. Hill, et al. (2017). "Naloxone Counseling for Harm Reduction and Patient Engagement." Fam Med 49(9): 730-733.

                BACKGROUND AND OBJECTIVES: The United States is experiencing an epidemic of opioid-related deaths. Naloxone, the drug of choice for reversing acute opioid overdose, is not routinely prescribed for outpatient use. The aims of this project were to improve naloxone awareness, increase naloxone prescribing, and prevent opioid overdoses. METHODS: A naloxone counseling intervention was implemented in three family health centers by an interprofessional team of providers including family medicine physicians, clinical pharmacists, and social workers. An outreach letter was designed with provider input, an electronic order set was developed to facilitate prescribing, and intranasal naloxone kits were assembled for free dispensing. Providers and staff received education about opioid overdose and naloxone prescribing. Faculty and resident physicians were surveyed before and after the intervention to assess their attitudes. Patients who received naloxone kits were surveyed to assess their attitudes and use of opioids and naloxone. RESULTS: Over 16 months, 71 outreach letters were distributed and 97 naloxone kits were dispensed. The majority of kits were prescribed for illicit opioid use. Faculty and resident physician surveys indicated improved knowledge about naloxone prescribing, and increased professional satisfaction caring for patients requesting opioids. Surveyed patients endorsed high levels of comfort discussing opioid use with their primary care physician. Five successful opioid overdose reversals were reported. CONCLUSIONS: An interprofessional naloxone counseling intervention engaged patients in opioid use discussions, increased provider satisfaction, and reversed overdoses. Improving naloxone access is an essential component of comprehensive overdose prevention programs that encourage responsible opioid prescribing and use.

Hussain, A., R. Kimura, et al. (1984). "Nasal absorption  of naloxone and buprenorphine in rats." Int J Pharm 21: 233-237.

            These authors measured bioavailabillity of naloxone via the IV and the intranasal route in rats and found that the peak levels of naloxone were similar and the bioavailability of naloxone intranasally was 100% (the same) of that available IV.

Kelen, G. D., G. B. Green, et al. (1992). "Hepatitis B and hepatitis C in emergency department patients." N Engl J Med 326(21): 1399-404.

Kelly, Am, et al. (2005). "Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose." Med J Aust 182(1): 24-7.

            OBJECTIVE: To determine the effectiveness of intranasal (IN) naloxone compared with intramuscular (IM) naloxone for treatment of respiratory depression due to suspected opiate overdose in the prehospital setting. DESIGN: Prospective, randomised, unblinded trial of either 2 mg naloxone injected intramuscularly or 2 mg naloxone delivered intranasally with a mucosal atomiser. PARTICIPANTS AND SETTING: 155 patients (71 IM and 84 IN) requiring treatment for suspected opiate overdose and attended by paramedics of the Metropolitan Ambulance Service (MAS) and Rural Ambulance Victoria (RAV) in Victoria. MAIN OUTCOME MEASURES: Response time to regain a respiratory rate greater than 10 per minute. Secondary outcome measures were proportion of patients with respiratory rate greater than 10 per minute at 8 minutes and/or a GCS score over 11 at 8 minutes; proportion requiring rescue naloxone; rate of adverse events; proportion of the IN group for whom IN naloxone alone was sufficient treatment. RESULTS: The IM group had more rapid response than the IN group, and were more likely to have more than 10 spontaneous respirations per minute within 8 minutes (82% v 63%; P = 0.0173). There was no statistically significant difference between the IM and IN groups for needing rescue naloxone (13% [IM group] v 26% [IN group]; P = 0.0558). There were no major adverse events. For patients treated with IN naloxone, this was sufficient to reverse opiate toxicity in 74%. CONCLUSION: IN naloxone is effective in treating opiate-induced respiratory depression, but is not as effective as IM naloxone. IN delivery of naxolone could reduce the risk of needlestick injury to ambulance officers and, being relatively safe to make more widely available, could increase access to life-saving treatment in the community.

Kerr, D., A. M. Kelly, et al. (2009). "Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose." Addiction 104(12): 2067-74.

            AIMS: Traditionally, the opiate antagonist naloxone has been administered parenterally; however, intranasal (i.n.) administration has the potential to reduce the risk of needlestick injury. This is important when working with populations known to have a high prevalence of blood-borne viruses. Preliminary research suggests that i.n. administration might be effective, but suboptimal naloxone solutions were used. This study compared the effectiveness of concentrated (2 mg/ml) i.n. naloxone to intramuscular (i.m.) naloxone for suspected opiate overdose. METHODS: This randomized controlled trial included patients treated for suspected opiate overdose in the pre-hospital setting. Patients received 2 mg of either i.n. or i.m. naloxone. The primary outcome was the proportion of patients who responded within 10 minutes of naloxone treatment. Secondary outcomes included time to adequate response and requirement for supplementary naloxone. Data were analysed using multivariate statistical techniques. RESULTS: A total of 172 patients were enrolled into the study. Median age was 29 years and 74% were male. Rates of response within 10 minutes were similar: i.n. naloxone (60/83, 72.3%) compared with i.m. naloxone (69/89, 77.5%) [difference: -5.2%, 95% confidence interval (CI) -18.2 to 7.7]. No difference was observed in mean response time (i.n.: 8.0, i.m.: 7.9 minutes; difference 0.1, 95% CI -1.3 to 1.5). Supplementary naloxone was administered to fewer patients who received i.m. naloxone (i.n.: 18.1%; i.m.: 4.5%) (difference: 13.6%, 95% CI 4.2-22.9). CONCLUSIONS: Concentrated intranasal naloxone reversed heroin overdose successfully in 82% of patients. Time to adequate response was the same for both routes, suggesting that the i.n. route of administration is of similar effectiveness to the i.m. route as a first-line treatment for heroin overdose.

Klebacher, R., M. I. Harris, et al. (2017). "Incidence of Naloxone Redosing in the Age of the New Opioid Epidemic." Prehosp Emerg Care: 1-6.

                STUDY OBJECTIVE: Naloxone, an opioid-antagonist deliverable by an intra-nasal route, has become widely available and utilized by law enforcement officers as well as basic life support (BLS) providers in the prehospital setting. This study aimed to determine the frequency of repeat naloxone dosing in suspected narcotic overdose (OD) patients and identify patient characteristics. METHODS: A retrospective chart review of patients over 17 years of age with suspected opioid overdose, treated with an initial intranasal (IN) dose of naloxone and subsequently managed by paramedics, was performed from April 2014 to June 2016. Demographic data was analyzed using descriptive statistics to identify those aspects of the history, physical exam findings. Results: A sample size of 2166 patients with suspected opioid OD received naloxone from first responders. No patients who achieved GCS 15 after treatment required redosing; 195 (9%) received two doses and 53 patients received three doses of naloxone by advanced life support. Patients were primarily male (75.4%), Caucasian (88.2%), with a mean age of 36.4 years. A total of 76.7% of patients were found in the home, 23.1% had a suspected mixed ingestion, and 27.2% had a previous OD. Two percent of all patients required a third dose of naloxone. CONCLUSION: In this prehospital study, we confirmed that intranasal naloxone is effective in reversing suspected opioid toxicity. Nine percent of patients required two or more doses of naloxone to achieve clinical reversal of suspected opioid toxicity. Two percent of patients received a third dose of naloxone.

Kobayashi, L., T. C. Green, et al. (2017). "Patient Simulation for Assessment of Layperson Management of Opioid Overdose With Intranasal Naloxone in a Recently Released Prisoner Cohort." Simul Healthc 12(1): 22-27.

                INTRODUCTION: Investigators applied simulation to an experimental program that educated, trained, and assessed at-risk, volunteering prisoners on opioid overdose (OD) prevention, recognition, and layperson management with intranasal (IN) naloxone. METHODS: Consenting inmates were assessed for OD-related experience and knowledge then exposed on-site to standardized didactics and educational DVD (without simulation). Subjects were provided with IN naloxone kits at time of release and scheduled for postrelease assessment. At follow-up, the subjects were evaluated for their performance of layperson opioid OD resuscitative skills during video-recorded simulations. Two investigators independently scored each subject's resuscitative actions with a 21-item checklist; post hoc video reviews were separately completed to adjudicate subjects' interactions for overall benefit or harm. RESULTS: One hundred three prisoners completed the baseline assessment and study intervention and then were prescribed IN naloxone kits. One-month follow-up and simulation data were available for 85 subjects (82.5% of trained recruits) who had been released and resided in the community. Subjects' simulation checklist median score was 12.0 (interquartile range, 11.0-15.0) of 21 total indicated actions. Forty-four participants (51.8%) correctly administered naloxone; 16 additional subjects (18.8%) suboptimally administered naloxone. Nonindicated actions, primarily chest compressions, were observed in 49.4% of simulations. Simulated resuscitative actions by 80 subjects (94.1%) were determined post hoc to be beneficial overall for patients overdosing on opioids. CONCLUSIONS: As part of an opioid OD prevention research program for at-risk inmates, investigators applied simulation to 1-month follow-up assessments of knowledge retention and skills acquisition in postrelease participants. Simulation supplemented traditional research tools for investigation of layperson OD management.

Krieter, P., N. Chiang, et al. (2016). "Pharmacokinetic Properties and Human Use Characteristics of an FDA-Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose." J Clin Pharmacol 56(10): 1243-1253.

Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose.

Krieter, P. A., C. N. Chiang, et al. (2019). "Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA-Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device." J Clin Pharmacol 59(8): 1078-1084.

For more than a decade, first responders and the general public have been able to treat suspected opioid overdoses using an improvised nasal naloxone device (INND) constructed from a prefilled syringe containing 2 mg of naloxone (1 mg/mL) attached to a mucosal atomization device. In recent years, the U.S. Food and Drug Administration (FDA)-approved Ezvio, an autoinjector that delivers 2 mg by intramuscular injection and Narcan nasal spray (2- and 4-mg strengths; 0.1 mL/dose) for the emergency treatment of a known or suspected opioid overdose. The present study was conducted to compare the pharmacokinetics of naloxone using the FDA-approved devices (each administered once) and either 1 or 2 administrations using the INND. When naloxone was administered twice using the improvised device, the doses were separated by 2 minutes. The highest maximum plasma concentration was achieved using the 4-mg FDA-approved spray. The highest exposures at 5 minutes postdose, based on AUC values, were after administration with the autoinjector and the 4-mg FDA-approved spray; at 10, 15, and 20 minutes postdose, the latter yielded the greatest exposure. Even after 2 administrations, the INND failed to achieve naloxone plasma levels comparable to the FDA-approved devices at any time. The ease of use and higher plasma concentrations achieved using the 4-mg FDA-approved spray, compared with the INND, should be considered when deciding which naloxone device to use.

Lenton, S., P. Dietze, et al. (2014). "Working together: Expanding the availability of naloxone for peer administration to prevent opioid overdose deaths in the Australian Capital Territory and beyond." Drug Alcohol Rev.34(4): 404-411.

ISSUE: Since the mid-1990s, there have been calls to make naloxone, a prescription-only medicine in many countries, available to heroin and other opioid users and their peers and family members to prevent overdose deaths. CONTEXT: In Australia there were calls for a trial of peer naloxone in 2000, yet at the end of that year, heroin availability and harm rapidly declined, and a trial did not proceed. In other countries, a number of peer naloxone programs have been successfully implemented. Although a controlled trial had not been conducted, evidence of program implementation demonstrated that trained injecting drug-using peers and others could successfully administer naloxone to reverse heroin overdose, with few, if any, adverse effects. APPROACH: In 2009 Australian drug researchers advocated the broader availability of naloxone for peer administration in cases of opioid overdose. Industrious local advocacy and program development work by a number of stakeholders, notably by the Canberra Alliance for Harm Minimisation and Advocacy, a drug user organisation, contributed to the rollout of Australia's first prescription naloxone program in the Australian Capital Territory (ACT). Over the subsequent 18 months, prescription naloxone programs were commenced in four other Australian states. IMPLICATIONS: The development of Australia's first take-home naloxone program in the ACT has been an 'ice-breaker' for development of other Australian programs. Issues to be addressed to facilitate future scale-up of naloxone programs concern scheduling and cost, legal protections for lay administration, prescribing as a barrier to scale-up; intranasal administration, administration by service providers and collaboration between stakeholders.

Loimer, N., P. Hofmann, et al. (1994). "Nasal administration of naloxone is as effective as the intravenous route in opiate addicts." Int J Addict 29(6): 819-27.

            Naloxone is used intravenously in opiate addiction in emergency cases, in rapid opiate detoxification, and as a diagnostic tool. This is a study comparing the efficacy of intranasal naloxone to other routes (intravenous/intramuscular) in 17 opiate-dependent patients. The nasal drug administration of naloxone was found to be as effective as the intravenous route. The nasal drug application offers a wide margin of safety for patients and medical staff, especially in emergency situations in regard to infection risks associated with vessel puncture.

Madah-Amiri, D., L. Gjersing, et al. (2019). "Naloxone distribution and possession following a large-scale naloxone programme." Addiction 114(1): 92-100.

AIMS: To examine uptake following a large-scale naloxone programme by estimating distribution rates since programme initiation and the proportion among a sample of high-risk individuals who had attended naloxone training, currently possessed or had used naloxone. We also estimated the likelihood of naloxone possession and use as a function of programme duration, individual descriptive and substance use indicators. DESIGN: (1) Distribution data (June 2014-August 2017) and date of implementation for each city and (2) a cross-sectional study among a sample of illicit substance users interviewed September 2017. SETTING: Seven Norwegian cities. PARTICIPANTS: A total of 497 recruited users of illegal opioids and/or central stimulants. MEASUREMENTS: Primary outcomes: naloxone possession and use. Random-intercepts logistic regression models (covariates: male, age, homelessness/shelter use, overdose, incarceration, opioid maintenance treatment, income sources, substance use indicators, programme duration). FINDINGS: Overall, 4631 naloxone nasal sprays were distributed in the two pilot cities, with a cumulative rate of 495 per 100 000 population. In the same two cities, among high-risk individuals, 44% and 62% reported current naloxone possession. The possession rates of naloxone corresponded well to the duration of each participating city's distribution programme. Overall, in the six distributing cities, 58% reported naloxone training, 43% current possession and 15% naloxone use. The significant indicators for possession were programme duration [adjusted odds ratios (aOR) = 1.44, 95% confidence interval (CI = 0.82-2.37], female gender (aOR = 1.97, 95% CI = 1.20-3.24) and drug-dealing (aOR = 2.36, 95% CI = 1.42-3.93). The significant indicators for naloxone use were programme duration (aOR = 1.49 95%, CI = 1.15-1.92), homelessness/shelter use (aOR = 2.06, 95% CI = 1.02-4.17), opioid maintenance treatment (OMT) (aOR = 2.07, 95% CI = 1.13-3.78), drug-dealing (aOR = 2.40, 95% CI = 1.27-4.54) and heroin injecting (aOR = 2.13, 95% CI = 1.04-4.38). CONCLUSIONS: A large-scale naloxone programme in seven Norwegian cities with a cumulative distribution rate of 495 per 100 000 population indicated good saturation in a sample of high-risk individuals, with programme duration in each city as an important indicator for naloxone possession and use.

Mahonski, S. G., J. B. Leonard, et al. (2019). "Prepacked naloxone administration for suspected opioid overdose in the era of illicitly manufactured fentanyl: a retrospective study of regional poison center data." Clin Toxicol (Phila): 1-7.

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.

Marcus, R., D. H. Culver, et al. (1993). "Risk of human immunodeficiency virus infection among emergency department workers." Am J Med 94(4): 363-70.

            PURPOSE: To estimate (1) the prevalence of human immunodeficiency virus (HIV) infection in emergency department (ED) patients, (2) the frequency of blood contact (BC) in ED workers (EDWs), (3) the efficacy of gloves in preventing BC, and (4) the risk of HIV infection in EDWs due to BC. PATIENTS AND METHODS: We conducted an 8-month study in three pairs of inner-city and suburban hospital EDs in high AIDS incidence areas in the United States. At each hospital, blood specimens from approximately 3,400 ED patients were tested for HIV antibody. Observers monitored BC and glove use by EDWs. RESULTS: HIV seroprevalence was 4.1 to 8.9 per 100 patient visits in the 3 inner-city EDs, 6.1 in 1 suburban ED, and 0.2 and 0.7 in the other 2 suburban EDs. The HIV infection status of 69% of the infected patients was unknown to ED staff. Seroprevalence rates were highest among patients aged 15 to 44 years, males, blacks and Hispanics, and patients with pneumonia. BC was observed in 379 (3.9%) of 9,793 procedures; 362 (95%) of the BCs were on skin, 11 (3%) were on mucous membranes, and 6 (2%) were percutaneous. Overall procedure-adjusted skin BC rates were 11.2 BCs per 100 procedures for ungloved workers and 1.3 for gloved EDWs (relative risk = 8.8; 95% confidence interval = 7.3 to 10.3). In the high HIV seroprevalence EDs studied, 1 in every 40 full-time ED physicians or nurses can expect an HIV-positive percutaneous BC annually; in the low HIV seroprevalence EDs studied, 1 in every 575. The annual occupational risk of HIV infection for an individual ED physician or nurse from performing procedures observed in this study is estimated as 0.008% to 0.026% (1 in 13,100 to 1 in 3,800) in a high HIV seroprevalence area and 0.0005% to 0.002% (1 in 187,000 to 1 in 55,000) in a low HIV seroprevalence area. CONCLUSIONS: In both inner-city and suburban EDs, patient HIV seroprevalence varies with patient demographics and clinical presentation; the infection status of most HIV-positive patients is unknown to ED staff. The risk to an EDW of occupationally acquiring HIV infection varies by ED location and the nature and frequency of BC; this risk can be reduced by adherence to universal precautions.

Marcus, R., P. U. Srivastava, et al. (1995). "Occupational blood contact among prehospital providers." Ann Emerg Med 25(6): 776-9.

            STUDY OBJECTIVE: To assess the nature and frequency of blood contact (BC) among emergency medical service (EMS) workers. DESIGN: During an 8-month period, we interviewed EMS workers returning from emergency transport calls on a sample of shifts. We simultaneously conducted an HIV seroprevalence survey among EMS-transported patients at receiving hospitals served by these workers. SETTING: Three US cities with high AIDS incidence. PARTICIPANTS: EMS workers. RESULTS: During 165 shifts, 2,472 patients were attended. Sixty-two BCs (1 needlestick and 61 skin contacts) were reported. Individual EMS workers had a mean of 1.25 BCs, including .02 percutaneous exposures, per 100 patients attended. The estimated annual frequency of BC for an EMS worker at the study sites was 12.3, including .2 percutaneous exposures. For 93.5% of the BCs, the HIV serostatus of the source patients was unknown to the EMS worker. HIV seroprevalences among EMS-transported patients at the three receiving hospital emergency departments were 8.3, 7.7, and 4.1 per 100 patients; the highest rates were among male patients 15 to 44 years old who presented with pneumonia. CONCLUSION: EMS personnel regularly experience BCs, most of which are skin contacts. Because the HIV serostatus of the patient is usually unknown, EMS workers should practice universal precautions. Postexposure management should include a mechanism for voluntary HIV counseling and testing of the patient after transport and transmittal of the results to the EMS.

Martin, T. G. (2003). "Take home naloxone: feasability, safety and efficacy." J Toxicol Clin Toxicol 41(4): 415-416.

            Fatal and nonfatal opiate overdose (OD) occur at a high or increasing higher rate in many parts of the world. Unintentional fatal opiate OD in opiate abusers is usually due to heroin but sometimes also methadone and buprenorphine. Sedative hypnotic coingestants especially ethanol or benzodiazepines, reduced tolerance from voluntary or forced abstinence (jail) and increased purity contribute to increase opiate-related mortality. Opiate abusers who witness an OD may not summon EMS because they don¹t trust them and fear police who often respond with them. Police may arrest and charge opiate abusers for outstanding warrants, possession, or murder if they supplied or injected the illicit substances1. EMS staff may transport users to the hospital involuntarily and/or give larger than necessary doses of naloxone to ensure a rapid reversal and less risk of renarcotization. Opiate abusers often attempt ineffective street remedies before summoning help. Take home naloxone was first suggested by Strang in 1992 to minimize the harm from opiate misuse2. To be feasible, take home naloxone programs must be acceptable to opiate abusers and prescribing physicians, affordable, easily teachable and applicable at opiate OD scenes. Most opiate abusers would favor taking home naloxone, would keep it in their home and use it if it were available3. The legal risk for U.S. physicians who prescribe naloxone for laypersons was judged to be low for those who act in good faith, in the course of professional practice and for a legitimate medical purpose1. Take home naloxone programs are feasible. Dispensing naloxone should be preceded by education that includes the purpose of naloxone use, potential adverse effects, recognizing serious opiate OD, indications for and technique of use, summoning EMS, reporting outcome and getting more naloxone. The education program should be designed for naloxone use on a fellow opiate abuser or by friends or family on the recipient. Mouth-to-mouth or cardiopulmonary resuscitation instructions are optional. Recipients should be taught to suspect a serious OD if heroin or other opiate has been used within the past 3h and the user is blue, unresponsive to vigorous stimulation, or cannot maintain arousal without constant or frequent stimulation. Naloxone is indicated for opiate OD who is unresponsive to vigorous stimulation. EMS should be summoned whenever naloxone is given, when arousal cannot be maintained without constant or frequent stimulation or when ³nodding off² is occurring and a responsible observer cannot remain present. The optimal route for layperson naloxone would be easy to learn and perform, with minimal risk of injury to the victim and rescuer, facilitates rapid onset of arousal but not abrupt withdrawal and needs little to no special equipment. The IM, SQ and intranasal (IN) routes appear to have the most attractive risk benefit and cost considerations. The IN route requires a special aerosol-generating device. The duration of action of IV naloxone was found to be substantially less than combined IV/IM naloxone (90 vs >360 min, respectively) in reversing morphineinduced respiratory depression4. In a comparison of SQ vs IV naloxone, the overall time to arousal was nearly identical (9.6 vs 9.3 min, respectively) with the slightly longer onset of action for SQ balanced by the slightly longer time required start the IV5. The IM and SQ routes could be considered as Œinjected¹ routes and taught as a deep injection. For the Œinjected¹ route (SQ or IM), 0.8 to 1.0 mg and for the IN route 2mg are the recommended initial doses. The risks and benefits of take home naloxone programs must be carefully considered. Arousal of heroin OD victims from layperson naloxone use could result in a larger proportion of victims leaving the scene prior to EMS arrival or against medical advice (AMA) afterwards. Because naloxone appears to have a shorter duration of effect than heroin, serious renarcotization may occur. The SQ, IM, or IN routes lead to slower absorption and a reduced risk of renarcotization. Abrupt reversal of CNS depression without prior correction of hypoxia and hypercarbia may result in greater catecholamine levels and risks of adverse sequela. Naloxone can precipitate acute withdrawal resulting in combative or agitated behavior. The slower onset and less severe withdrawal from IM, SQ and IN routes lower the risk of adverse reactions to naloxone. While there is concern that lowering the risk of death will remove an important deterrent, many believe that opiate abuse is not deterred by risk of bodily harm or death. Many experts believe that naloxone misuse by opiate abusers is very unlikely to occur and early evidence from feasibility trials substantiate this belief6. The sooner that the respiratory failure is corrected the less likely it will cause pulmonary edema, hypoxic encephalopathy or death. There are scant published data available to judge its efficacy or safety. In Berlin, naloxone, supplies, and instructions were dispensed to 124 opiate abusers. They reported that 22 users gave naloxone on 27 occasions; IM on 14 (48%), IV on 13 (45%) and SQ on 2 (7%). Naloxone use appeared to be appropriate in 26 (90%), of dubious benefit in 2 (7%) and inappropriate (cocaine OD) on 1 (4%) occasion7. In Jersey, a minijet prefilled with naloxone along and training were given to 101opiate abusers resulting in 5 successful resuscitations7. In Chicago, naloxone has been distributed to over 550 opiate abusers with 52 successful uses reported8. In Can Tunis, Spain, naloxone is being provided along with brieftraining and 60 successful cases have been reported9. There are many challenges in designing a trial to determine the effectiveness of take home naloxone programs. Since naloxone use in these circumstances is a life-saving therapy, it would be unethical to randomize therapy between naloxone and a placebo treatment. These challenges must be overcome and higher-quality data provided before the effectiveness and safety of take home naloxone programs can be assessed. References: 1. Burris S, Norland J, Edlin BR. Legal aspects of providing naloxone to heroin users in the United States. Int J Drug Policy 2001;12:237248. 2. Strang J, Farrell M. Harm minimisation for drug misusers. BMJ 1992;304:11278. 3. Strang J, Powis B, Best D et al. Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability. Addiction 1999;94:199204. 4. Longnecker DE, Grazis PA, Eggers GWN. Naloxone for antagonism of morphine-induced respiratory depression. Anesth Analg 1973;52:447453. 5. Wanger K, Brough L, Macmillan I et al. Intravenous vs. subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med 1998;5:293299. 6. Darke S, Hall W. The distribution of naloxone to heroin users. Addiction 1997;92:11959. 7. Dettmer K, Saunders B, Strang J. Take home naloxone and the prevention of deaths from opiate overdose: two pilot schemes. BMJ 2001;322:8956. 8. Bigg D. Data on take home naloxone are unclear but not condemnatory. (Editorial) BMJ 2002;324:678. 9. Trujols J. Take home naloxone: Life-saving intervention, medico-legal concern and heroin user¹s competence. (Editorial) BMJ.COM Rapid Responses 13 May 2001.

McDonald, R., O. Danielsson Glende, et al. (2018). "International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database." Drug Alcohol Rev 37(2): 205-215.

ISSUES: Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. APPROACH: (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'. KEY FINDINGS: Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40 mg mL(-1) ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non-concentrated intranasal spray (1 mg mL(-1) ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (>/=10 mg mL(-1) ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted Cmax = 0.8-1.7 ng mL(-1) ) reached in 19-30 min (tmax ). IMPLICATIONS: Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. CONCLUSION: We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende O, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000-000].

McDonald, R., U. Lorch, et al. (2018). "Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study." Addiction 113(3): 484-493.

BACKGROUND AND AIMS: Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability. DESIGN: Open-label, randomized, five-way cross-over PK study. SETTING: Clinical trials facility (Croydon, UK). PARTICIPANTS: Thirty-eight healthy volunteers (age 20-54 years; 11 female). INTERVENTION AND COMPARATOR: Three doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone. MEASUREMENTS: Regular blood samples were taken, with high-frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration. FINDINGS: Mean peak concentration (Cmax ) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15-30 minutes (Tmax ). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47-51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 x 2 mg i.n. versus 5 x 0.4 mg i.m. doses) at 3-minute intervals showed that comparable plasma naloxone concentrations would be anticipated. CONCLUSIONS: Concentrated 2 mg intranasal naloxone is well-absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post-dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.

Open access:

Merlin M.A., Saybolt M., Kapitanyan R, et al (2009) "Intranasal naloxone delivery is an alternative to intravenoius naloxone for opioid overdoses." Am J Emerg Med - published online Oct 2009, pending journal publication

Introduction - This study proposes that intranasal (IN) naloxone administration is preferable to intravenous (IV) naloxone by emergency medical services for opioid overdoses. Our study attempts to establish that IN naloxone is as effective as IV naloxone but without the risk of needle exposure. We also attempt to validate the use of the Glasgow Coma Scale (GCS) in opioid intoxication. Methods - A retrospective chart review of prehospital advanced life support patients was performed on confirmed opioid overdose patients. Initial and final unassisted respiratory rates (RR) and GCS, recorded by paramedics, were used as indicators of naloxone effectiveness. The median changes in RR and GCS were determined. Results-Three hundred forty-four patients who received naloxone by paramedics from January 1, 2005, until December 31, 2007, were evaluated. Of confirmed opioid overdoses, change in RR was 6 for the IV group and 4 for the IN group (P = .08). Change in GCS was 4 for the IV group and 3 for the IN group (P = .19). Correlations between RR and GCS for initial, final, and change were significant at the 0.01 level (ρ = 0.577, 0.462, 0.568, respectively). Conclusion: Intranasal naloxone is statistically as effective as IV naloxone at reversing the effects of opioid overdose. The IV and IN groups had similar average increases in RR and GCS. Based on our results, IN naloxone is a viable alternative to IV naloxone while posing less risk of needle stick injury. Additionally, we demonstrated that GCS is correlated with RR in opioid intoxication.

McDermott, C. and N. C. Collins (2012). "Prehospital medication administration: a randomised study comparing intranasal and intravenous routes." Emerg Med Int 2012: 476161.

Introduction. Opioid overdose is an ever-increasing problem globally. Recent studies have demonstrated that intranasal (IN) naloxone is a safe and effective alternative to traditional routes of naloxone administration for reversal of opioid overdose. Aims. This randomised controlled trial aimed to compare the time taken to deliver intranasal medication with that of intravenous (IV) medication by advanced paramedic trainees. Methods. 18 advanced paramedic trainees administered either an IN or IV medication to a mannequin model in a classroom-based setting. The time taken for medication delivery was compared. End-user satisfaction was assessed using a 5-point questionnaire regarding ease of use and safety for both routes. Results. The mean time taken for the IN and IV group was 87.1 seconds and 178.2 seconds respectively. The difference in mean time taken was 91.1 seconds (95% confidence interval 55.2 seconds to 126.9 seconds, P </= 0.0001). 89% of advanced paramedic trainees reported that the IN route was easier and safer to use than the IV route. Conclusion. This study demonstrates that, amongst advanced paramedic trainees, the IN route of medication administration is significantly faster, better accepted and perceived to be safer than using the IV route. Thus, IN medication administration could be considered more frequently when administering emergency medications in a pre-hospital setting.

Neale, J., C. Brown, et al. (2018). "How competent are people who use opioids at responding to overdoses? Qualitative analyses of actions and decisions taken during overdose emergencies." Addiction.

BACKGROUND AND AIMS: Providing take-home naloxone (THN) to people who use opioids is an increasingly common strategy for reversing opioid overdose. However, implementation is hindered by doubts regarding the ability of people who use opioids to administer naloxone and respond appropriately to overdoses. We aimed to increase understanding of the competencies required and demonstrated by opioid users who had recently participated in a THN programme and were subsequently confronted with an overdose emergency. DESIGN: Qualitative study designed to supplement findings from a randomized controlled trial of overdose education and naloxone distribution. Interviews were audio-recorded, transcribed, systematically coded and analysed via Iterative Categorization. SETTING: New York City, USA. PARTICIPANTS: Thirty-nine people who used opioids (32 men, 7 women; aged 22-58 years). INTERVENTION: Trial participants received brief or extended overdose training and injectable or nasal naloxone. MEASUREMENTS: The systematic coding frame comprised deductive codes based on the topic guide and more inductive codes emerging from the data. FINDINGS: In 38 of 39 cases the victim was successfully resuscitated; the outcome of one overdose intervention was unknown. Analyses revealed five core overdose response 'tasks': (1) overdose identification; (2) mobilizing support; (3) following basic first aid instructions; (4) naloxone administration; and (5) post-resuscitation management. These tasks comprised actions and decisions that were themselves affected by diverse cognitive, emotional, experiential, interpersonal and social factors over which lay responders often had little control. Despite this, participants demonstrated high levels of competency. They had acquired new skills and knowledge through training and brought critical 'insider' understanding to overdose events and the resuscitation actions which they applied. CONCLUSIONS: People who use opioids can be trained to respond appropriately to opioid overdoses and thus to save their peers' lives. Overdose response requires both practical competency (e.g. skills and knowledge in administering basic first aid and naloxone) and social competency (e.g. willingness to help others, having the confidence to be authoritative and make decisions, communicating effectively and demonstrating compassion and care to victims post-resuscitation).

Osterwalder, J. J. (1995). "Patients intoxicated with heroin or heroin mixtures: how long should they be monitored?" Eur J Emerg Med 2(2): 97-101.

            Our investigation was carried out in subjects intoxicated with heroin or heroin mixtures to find out the time interval during which delayed life-threatening complications become manifest, such as pulmonary oedema or relapse into respiratory depression or coma after naloxone treatment. We studied prospectively all drug intoxications between 1991 and 1992. Of the 538 intoxications, we assessed in detail 160 outpatients who lived within the catchment area of our hospital. The outcome variables studied were (1) rehospitalization for pulmonary oedema, (2) relapse into coma, and/or (3) death and cause within 24 h after release from hospital. Deaths occurring outside our hospital have to be reported, as decreed by law, to the Institute for Forensic Medicine. The results of our investigation showed no rehospitalization owing to pulmonary oedema or coma, but one death, outside the hospital, owing to delayed pulmonary oedema. This delayed complication had an incidence of 0.6% (95% confidence interval 0-3.8%). A reintoxication could be excluded in this patient. Based on reliable report, the pulmonary oedema occurred between approximately 2 1/4 and 8 1/4 hours after intoxication. In the literature, only two cases of delayed pulmonary oedema have been reported with reliable time statements (4 and 6 h after hospitalization). We therefore conclude that surveillance for at least 8 h is essential after successful treatment to exclude delayed pulmonary oedema in patients intoxicated with heroin or heroin mixtures.

Parkin, J. M., M. Murphy, et al. (2000). "Tolerability and side-effects of post-exposure prophylaxis for HIV infection." Lancet 355(9205): 722-3.

            A study of HIV post-exposure prophylaxis in 28 recipients showed that indinavir-containing regimens were poorly tolerated. This finding has implications for compliance and efficacy of the currently recommended combinations.

Pepe, P. E., F. B. Hollinger, et al. (1986). "Viral hepatitis risk in urban emergency medical services personnel." Ann Emerg Med 15(4): 454-7.

            Houston has large groups of people known to be at high risk for hepatitis B virus (HBV) infection. Emergency medical services (EMS) personnel are continuously exposed to blood from these high-risk individuals. We sought to determine the prevalence of HBV infection in the city's EMS personnel. Of the 350 Houston firefighters assigned to EMS, 344 were surveyed by questionnaire and a blood specimen was obtained. Each sample was assayed by radio-immunoassay or enzyme-linked immunoassay for hepatitis A antibody (anti-HAV), hepatitis B surface antigen (HBsAg), and antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). A history of hepatitis was reported by 19 persons, 17 of whom had serologic evidence of infection with HAV (56%), HBV (26%), or both diseases (11%). The anti-HAV prevalence was 16% (12% in whites and 35% in nonwhites; P less than .001). No correlation was observed with years of occupational exposure. Of the 338 personnel evaluated for HBV seromarkers (six HBsAg-vaccinated subjects were excluded), 13% were positive; 0.6% had an active infection as determined by the presence of both HBsAg and anti-HBc; 6.8% were both anti-HBs and anti-HBc positive; 0.9% were positive for anti-HBc alone; and 4.7% of the sera contained only anti-HBs (all with geometric mean antibody levels of less than or equal to 13 mlU/mL). The 28 individuals (8.3%) whose sera contained anti-HBc were classified as cases of previous or concurrent HBV infection. A strong correlation (P less than .004) was observed between HBV infection and years of work exposure in EMS regardless of job description (paramedic versus emergency medical technician).(ABSTRACT TRUNCATED AT 250 WORDS)

Pietrusza, L. M., K. R. Puskar, et al. (2018). "Evaluation of an Opiate Overdose Educational Intervention and Naloxone Prescribing Program in Homeless Adults Who Use Opiates." J Addict Nurs 29(3): 188-195.

Opiate overdose deaths are considered an epidemic by the Centers for Disease Control and Prevention. Homeless adults are disproportionately affected by opioid overdoses. The purpose of this project was to implement an opiate overdose training and routine naloxone prescribing program for patients at a Health Care for the Homeless clinic. Education consisted of overdose risk factors, signs of overdose, how to respond to an opiate overdose, and how to administer naloxone. Knowledge was measured with a pretest and a posttest. Intranasal naloxone was prescribed for each person who received the education, and prescription fill rates were tracked 1 week after the clinic visit. Patients had a significant increase in knowledge, and the overall naloxone fill rate was 33%. Fill rates varied by housing, insurance, and other prescription status. Opiate overdose education can effectively be delivered in a homeless medical clinic, although more research is needed regarding barriers to naloxone fill rates.

Pruyn, S., J. Frey, et al. (2019). "Quality Assessment of Expired Naloxone Products from First-Responders' Supplies." Prehosp Emerg Care 23(5): 647-653.

Objective: Naloxone is an opioid receptor antagonist that reverses life-threatening effects of opioid overdose. Since the 1970s, naloxone products have been developed as injectable solutions, and more recently as nasal sprays. Naloxone products have saved many lives in emergency settings. These products are routinely carried by public safety first-responders including fire fighters (FF), law enforcement officers (LEO), and emergency medical services (EMS). Now, they are also distributed through community access programs to the public. While public safety medications are monitored, those publically distributed are not, so expired products can be possibly found on-hand in an emergency. This study analyzed the quality and stability of expired Naloxone HCl Solutions for Injection, to assess their remaining efficacies and potential risks. Methods: The samples were collected from EMS or law enforcement training supplies and expired returns, with expiration dates ranging from 1990 to 2018. Using standardized techniques, the remaining naloxone was quantified, and the main degradation products, nornaloxone (also known as noroxymorphone) and other possible species, were monitored and quantified systematically. Results: Most tested samples were found containing more than 90% of labeled naloxone, including those stored for nearly 30 years. The naloxone degradation was slow, but generally correlated with storage time length. There was no significant amount of degradation products detected across all samples. Nornaloxone was detected from some older samples, but all less than 1%. Therefore, although it is an opioid agonist, the risk caused by nornaloxone should be low. Conclusion: This quality assessment demonstrates that expired naloxone products may still meet USP standards, even after many years. Further pharmaceutical, clinical, and regulatory investigation should be conducted to confirm our findings, especially for new naloxone products with different formulations and routes of administration. Extending the shelf-life of naloxone products may have important financial and public health consequences in addressing future drug shortages and meeting the needs for this critical drug.

Rando, J., D. Broering, et al. (2015). "Intranasal naloxone administration by police first responders is associated with decreased opioid overdose deaths." Am J Emerg Med.

                OBJECTIVE: This study sought to answer the question, "Can police officers administer intranasal naloxone to drug overdose victims to decrease the opioid overdose death rate?" METHODS: This prospective interventional study was conducted in Lorain County, OH, from January 2011 to October 2014. Starting October 2013, trained police officers administered naloxone to suspected opioid overdose victims through a police officer naloxone prescription program (NPP). Those found by the county coroner to be positive for opioids at the time of death and those who received naloxone from police officers were included in this study. The rate of change in the total number of opioid-related deaths in Lorain County per quarter year, before and after initiation of the NPP, and the trend in the survival rate of overdose victims who were given naloxone were analyzed by linear regression. Significance was established a priori at P < .05. RESULTS: Data from 247 individuals were eligible for study inclusion. Opioid overdose deaths increased significantly before initiation of the police officer NPP with average deaths per quarter of 5.5 for 2011, 15.3 for 2012, and 16.3 for the first 9 months of 2013. After initiation of the police officer NPP, the number of opioid overdose deaths decreased each quarter with an overall average of 13.4. Of the 67 participants who received naloxone by police officers, 52 (77.6%) survived, and 8 (11.9%) were lost to follow-up. CONCLUSIONS: Intranasal naloxone administration by police first responders is associated with decreased deaths in opioid overdose victims.

Ray B, O'Donnell D, Kahre K. Police officer attitudes towards intranasal naloxone training. Drug Alcohol Depend 2015;146:107-10.

BACKGROUND: One approach to reduce fatal opioid overdose is by distributing naloxone to law enforcement officers. While several cities have implemented these naloxone programs, little research has investigated officer attitudes about their training. The present research attempts to fill this gap by analyzing survey data from police officers following intranasal naloxone training. METHODS: All of the police officers within the same district in Indianapolis, Indiana, underwent training to recognize opioid overdose and to administer intranasal naloxone (N=117). Following training, officers completed a survey that measured prior experience with opioid overdose, perceived importance of training, and items from the Opioid Overdose Attitudes Scale (OOAS) to measure attitudes following training. RESULTS: The officers had overwhelmingly positive feelings about the training, that it was not difficult, and that other officers should be trained to use naloxone. The OOAS items suggest that officers know the appropriate actions to take in the event of an overdose and feel that administering intranasal naloxone will not be difficult. Finally, we found that officers who had more experience with opioid overdose had more positive attitudes about the training. CONCLUSION: Distributing naloxone to police officers is likely a trend that will continue so it is important to understand how police officers respond to training to assure that future trainings are as effective as possible. Further research is needed to investigate the impact that these programs have on the community.

Richert, T. (2015). "Wasted, overdosed, or beyond saving - To act or not to act? Heroin users' views, assessments, and responses to witnessed overdoses in Malmo, Sweden." Int J Drug Policy 26(1): 92-99.

BACKGROUND: Overdose is a significant cause of death among heroin users. Frequently, other heroin users are present when an overdose occurs, which means the victim's life could be saved. There is a lack of studies that, based on heroin users own stories, examine their views, assessments, and responses to witnessed overdoses. METHODS: The study is based on qualitative interviews with thirty-five heroin users who witnessed someone else's overdose. RESULTS: The heroin users generally had a positive attitude towards assisting peers who had overdosed. A number of factors and circumstances, however, contribute to witnesses often experiencing resistance to or ambivalence about responding. The witness's own high, the difficulty in assessing the seriousness of the situation, an unwillingness to disturb someone else's high, uncertainty about the motive behind the overdose and whether the victim does or does not want assistance as well as fear of police involvement, were common factors that acted as barriers to adequate responses in overdose situations. CONCLUSION: The fact that being high makes it difficult to respond to overdoses, using traditional methods, argues for simpler and more effective response techniques. This can include intranasal naloxone programs for heroin users. The findings regarding the uncertainty about the intention of the overdose victim and the sensitivity to the experience of a good high argue for more up-front communication and discussion amongst using peers so that they can make their intentions clear to each other. Issues like this can be addressed in overdose education interventions. Overdose prevention measures also need to address the fact that fear of the police acts as a barrier to call emergency services.

Robertson, T. M., G. W. Hendey, et al. (2009). "Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose." Prehosp Emerg Care 13(4): 512-5.

            OBJECTIVE: To compare the prehospital time intervals from patient contact and medication administration to clinical response for intranasal (IN) versus intravenous (IV) naloxone in patients with suspected narcotic overdose. METHODS: This was a retrospective review of emergency medical services (EMS) and hospital records, before and after implementation of a protocol for administration of intranasal naloxone by the Central California EMS Agency. We included patients with suspected narcotic overdose treated in the prehospital setting over 17 months, between March 2003 and July 2004. Paramedics documented dose, route of administration, and positive response times using an electronic record. Clinical response was defined as an increase in respiratory rate (breaths/min) or Glasgow Coma Scale score of at least 6. Main outcome variables included time from medication to clinical response and time from patient contact to clinical response. Secondary variables included numbers of doses administered and rescue doses given by an alternate route. Between-group comparisons were accomplished using t-tests and chi-square tests as appropriate. RESULTS: One hundred fifty-four patients met the inclusion criteria, including 104 treated with IV and 50 treated with IN naloxone. Clinical response was noted in 33 (66%) and 58 (56%) of the IN and IV groups, respectively (p = 0.3). The mean time between naloxone administration and clinical response was longer for the IN group (12.9 vs. 8.1 min, p = 0.02). However, the mean times from patient contact to clinical response were not significantly different between the IN and IV groups (20.3 vs. 20.7 min, p = 0.9). More patients in the IN group received two doses of naloxone (34% vs. 18%, p = 0.05), and three patients in the IN group received a subsequent dose of IV or IM naloxone. CONCLUSIONS: The time from dose administration to clinical response for naloxone was longer for the IN route, but the overall time from patient contact to response was the same for the IV and IN routes. Given the difficulty and potential hazards in obtaining IV access in many patients with narcotic overdose, IN naloxone appears to be a useful and potentially safer alternative.

Rosenberg, M., G. Chai, et al. (2018). "Trends and economic drivers for United States naloxone pricing, January 2006 to February 2017." Addict Behav 86: 86-89.

Anecdotal evidence indicates that naloxone prices have risen in recent years, but limited research has examined the magnitude of these increases and potential causes. We contribute nationally representative evidence to help answer each of these questions, including wholesale pricing data from a proprietary drug sales database spanning January 2006 to February 2017. We find that all formulations of naloxone increased in price since 2006 except for Narcan Nasal Spray. These cumulative increases totaled 2281% for the 0.4 MG single-dose products, 244% for the 2 MG single-dose products, 3797% for the 4 MG multi-dose products, and 469% for the 0.4 MG Evzio auto-injector. We believe that increased demand for naloxone from the opioid epidemic may explain the more gradual price increases for the 0.4 MG single-dose and 4 MG multi-dose products prior to 2012. On the other hand, we believe that the sudden, sustained prices increases occurring for all of the products since 2012 may be the result of a drug shortage for the 0.4 MG single-dose products and the fact that each naloxone product has historically been sold by only a single competitor.

Sabzghabaee, A. M., N. Eizadi-Mood, et al. (2014). "Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial." Arch Med Sci 10(2): 309-314.

INTRODUCTION: This study was designed to compare the effects of intranasal (IN) and intravenous (IV) administration of naloxone in patients who had overdosed on opioids. MATERIAL AND METHODS: This randomized clinical trial study was conducted in the Department of Poisoning Emergencies at Noor and Ali Asghar (PBUH) University Hospital. One hundred opioid overdose patients were assigned by random allocation software into two study groups (n = 50). Both groups received 0.4 mg naloxone: one group IN and the other IV. Outcomes included change in the level of consciousness (measured using a descriptive scale and the Glasgow Coma Scale (GCS)), time to response, vital signs (blood pressure, heart rate and respiratory rate), arterial blood O2 saturation before and after naloxone administration, side-effects (agitation) and length of hospital stay. RESULTS: Patients who had been administered IN naloxone demonstrated significantly higher levels of consciousness than those in the IV group using both descriptive and GCS scales (p < 0.001). There was a significant difference in the heart rate between IN and IV groups (p = 0.003). However, blood pressure, respiratory rate and arterial O2 saturation were not significantly different between the two groups after naloxone administration (p = 0.18, p = 0.17, p = 0.32). There was also no significant difference in the length of hospital stay between the two groups (p = 0.14). CONCLUSIONS: Intranasal naloxone is as effective as IV naloxone in reversing both respiratory depression and depressive effects on the central nervous system caused by opioid overdose.

Samuels, E. (2014). "Emergency department naloxone distribution: a rhode island department of health, recovery community, and emergency department partnership to reduce opioid overdose deaths." R I Med J (2013) 97(10): 38-39.

In response to increasing rates of opioid overdose deaths in Rhode Island (RI, the RI Department of Health, RI emergency physicians, and Anchor Community Recovery Center designed an emergency department (ED) naloxone distribution and peer-recovery coach program for people at risk of opioid overdose. ED patients at risk for overdose are offered a take home naloxone kit, patient education video, and, when available, an Anchor peer recovery coach to provide recovery support and referral to treatment. In August 2014, the program launched at Kent, Miriam, and Rhode Island Hospital Emergency Departments. [Full text available at, free with no login].

Seal, K. H., M. Downing, et al. (2003). "Attitudes about prescribing take-home naloxone to injection drug users for the management of heroin overdose: a survey of street-recruited injectors in the San Francisco Bay Area." J Urban Health 80(2): 291-301.

Naloxone, an injectable opiate antagonist, can immediately reverse an opiate overdose and prevent overdose death. We sought to determine injection drug users' (IDUs) attitudes about being prescribed take-home naloxone. During November 1999 to February 2000, we surveyed 82 street-recruited IDUs from the San Francisco Bay Area of California who had experienced one or more heroin overdose events. We used a questionnaire that included structured and open-ended questions. Most respondents (89%) had witnessed an overdose, and 90% reported initially attempting lay remedies in an effort to help companions survive. Only 51% reported soliciting emergency assistance (calling 911) for the last witnessed overdose, with most hesitating due to fear of police involvement. Of IDUs surveyed, 87% were strongly in favor of participating in an overdose management training program to receive take-home naloxone and training in resuscitation techniques. Nevertheless, respondents expressed a variety of concerning attitudes. If provided naloxone, 35% predicted that they might feel comfortable using greater amounts of heroin, 62% might be less inclined to call 911 for an overdose, 30% might leave an overdose victim after naloxone resuscitation, and 46% might not be able to dissuade the victim from using heroin again to alleviate withdrawal symptoms induced by naloxone. Prescribing take-home naloxone to IDUs with training in its use and in resuscitation techniques may represent a life-saving, peer-based adjunct to accessing emergency services. Nevertheless, strategies for overcoming potential risks associated with the use of take-home naloxone would need to be emphasized in an overdose management training program.

Seal, K. H., R. Thawley, et al. (2005). "Naloxone distribution and cardiopulmonary resuscitation training for injection drug users to prevent heroin overdose death: a pilot intervention study." J Urban Health 82(2): 303-311.

Fatal heroin overdose has become a leading cause of death among injection drug users (IDUs). Several recent feasibility studies have concluded that naloxone distribution programs for heroin injectors should be implemented to decrease heroin over-dose deaths, but there have been no prospective trials of such programs in North America. This pilot study was undertaken to investigate the safety and feasibility of training injection drug using partners to perform cardiopulmonary resuscitation (CPR) and administer naloxone in the event of heroin overdose. During May and June 2001, 24 IDUs (12 pairs of injection partners) were recruited from street settings in San Francisco. Participants took part in 8-hour training in heroin overdose prevention, CPR, and the use of naloxone. Following the intervention, participants were prospectively followed for 6 months to determine the number and outcomes of witnessed heroin overdoses, outcomes of participant interventions, and changes in participants' knowledge of overdose and drug use behavior. Study participants witnessed 20 heroin overdose events during 6 months follow-up. They performed CPR in 16 (80%) events, administered naloxone in 15 (75%) and did one or the other in 19 (95%). All overdose victims survived. Knowledge about heroin overdose management increased, whereas heroin use decreased. IDUs can be trained to respond to heroin overdose emergencies by performing CPR and administering naloxone. Future research is needed to evaluate the effectiveness of this peer intervention to prevent fatal heroin overdose.

Skulberg, A. K., A. Asberg, et al. (2019). "Pharmacokinetics of a novel, approved, 1.4-mg intranasal naloxone formulation for reversal of opioid overdose-a randomized controlled trial." Addiction 114(5): 859-867.

BACKGROUND AND AIMS: Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxone. DESIGN: Open, randomized four-way cross-over trial. SETTING: Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. PARTICIPANTS: Twenty-two healthy human volunteers, 10 women, median age = 25.8 years. INTERVENTION AND COMPARATOR: One and two doses of i.n. 1.4 mg naloxone compared with i.m. 0.8 mg and intravenous (i.v.) 0.4 mg naloxone. MEASUREMENTS: Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non-compartment analyses were used for the main analyses. A non-parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. FINDINGS: Area under the curve from administration to last measured concentration (AUC0-last ) for i.n. 1.4 mg and i.m. 0.8 mg were 2.62 +/- 0.94 and 3.09 +/- 0.64 h x ng/ml, respectively (P = 0.33). Maximum concentration (Cmax ) was 2.36 +/- 0.68 ng/ml for i.n. 1.4 mg and 3.73 +/- 3.34 for i.m. 0.8 mg (P = 0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18 +/- 1.53 ng/ml. Tmax was reached after 20.2 +/- 9.4 minutes for i.n. 1.4 mg and 13.6 +/- 15.4 minutes for i.m. 0.8 mg (P = 0.098). The absolute bioavailability for i.n. 1.4 mg was 0.49 (+/-0.24), while the relative i.n./i.m. bioavailability was 0.52 (+/-0.25). CONCLUSION: Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals.

Smart, R., C. K. Geiger, et al. (2019). "An Observational Study of Retail Pharmacy Naloxone Prescriptions: Differences Across Provider Specialties and Patient Populations." J Gen Intern Med.

BACKGROUND: Despite exponential growth in pharmacy-dispensed naloxone, little information is available regarding variation in naloxone prescribing pattern across specialty groups, regions, and patient populations. OBJECTIVE: Explore variation in pharmacy-dispensed naloxone by prescriber specialty and patient characteristics. DESIGN: Cross-sectional analysis of the 2016 national retail pharmacy naloxone prescription claims from the IQVIA Real Longitudinal Prescriptions database. PARTICIPANTS: Naloxone prescribers and individuals filling naloxone prescriptions. MAIN MEASURES: Descriptive statistics assess differences across prescriber specialty groups in number of naloxone prescribers, patient and prescription characteristics, and geographic variation in naloxone dispensation and naloxone market share across prescriber specialty groups or formulation. KEY RESULTS: In 2016, 100,958 naloxone prescriptions written by 14,026 prescribers were filled by 88,735 patients. Primary care physicians accounted for the largest share of naloxone prescribers (45.9%); pain and anesthesia physicians and non-physicians prescribed to significantly greater numbers of patients (means of 10 and 8, respectively). While responsible for a relatively small share of naloxone dispensed (6.1%), psychiatrists and addiction specialists disproportionately served younger individuals, accounting for 49.5% of all prescriptions for individuals aged 35 and younger. Naloxone fill rates differed greatly across geographic regions, with the highest per capita rates in New England and the most concentrated prescribing in the West South Central and South Atlantic regions, where naloxone prescribers had the highest average numbers of patients (9.7 and 7.9, respectively). The South Atlantic and West South Central also had naloxone markets dominated by the Evzio(R) auto-injector, responsible for 50.3% and 43.8% of all naloxone dispensed in the regions; in contrast, New England's naloxone market was predominantly comprised of generic formulations (48.8%) and Narcan(R) nasal spray (45.4%). CONCLUSIONS: Our findings reflect a need to better understand barriers to uptake of naloxone prescribing behavior among physicians and other prescribers to ensure individuals have adequate opportunity to receive naloxone from their treating clinicians.

Smith, D. A., L. Leake, et al. (1992). "Is admission after intravenous heroin overdose necessary?" Ann Emerg Med 21(11): 1326-30.

            STUDY OBJECTIVES: To investigate the time of onset and incidence of complications in patients presenting to the emergency department with an IV heroin overdose and the need for routine admission of such patients. METHODS: A retrospective chart review of hospital and emergency medical service records of 124 patient visits involving IV heroin overdose over a five-month period. We also reviewed the death certificates of 115 persons having succumbed to a narcotic overdose over a 44-month period and compared these with our hospital records. SETTING: Urban county hospital. TYPE OF PARTICIPANTS: Patients presenting to the ED with an IV heroin overdose. RESULTS: There were five deaths in the ED, 12 hospital admissions, and 107 patients who were discharged home. Neither delayed onset of pulmonary edema nor recurrence of respiratory depression was observed. Of the 115 persons having succumbed to a narcotic overdose, eight had been seen previously at our hospital for a heroin overdose. There is no evidence that any of these eight deaths would have been prevented by a 24-hour hospital observation period. CONCLUSION: Complications arising from an IV overdose of heroin are usually evident on arrival in the ED or shortly thereafter. On retrospective review we have found no evidence that admission to the hospital and 24 hours of observation are of benefit to patients who are awake, alert, and lacking evidence of pulmonary complications after an IV heroin overdose.

Strang, J., R. McDonald, et al. (2016). "Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?" Addiction 111(4): 574-582.

CONTEXT: Take-home naloxone is increasingly provided to prevent heroin overdose deaths. Naloxone 0.4-2.0 mg is licensed for use by injection. Some clinicians supply improvised nasal naloxone kits (outside licensed approval). Is this acceptable? AIMS: (1) To consider provision of improvised nasal naloxone in clinical practice and (2) to search for evidence for pharmacokinetics and effectiveness (versus injection). METHODS: (1) To document existing nasal naloxone schemes and published evidence of pharmacokinetics (systematic search of the CINAHL, Cochrane, EMBASE and MEDLINE databases and 18 records included in narrative synthesis). (2) To analyse ongoing studies investigating nasal naloxone (WHO International Clinical Trials Registry Platform and US NIH RePORT databases). FINDINGS: (1) Multiple studies report overdose reversals following administration of improvised intranasal naloxone. (2) Overdose reversal after nasal naloxone is frequent but may not always occur. (3) Until late 2015, the only commercially available naloxone concentrations were 0.4 mg/ml and 2 mg/2 ml. Nasal medications are typically 0.05-0.25 ml of fluid per nostril. The only published study of pharmacokinetics and bioavailability finds that nasal naloxone has poor bioavailability. QUESTIONS FOR DEBATE: (1) Why are pharmacokinetics and bioavailability data for nasal naloxone not available before incorporation into standard clinical practice? (2) Does nasal naloxone have the potential to become a reliable clinical formulation? (3) What pre-clinical and clinical studies should precede utilization of novel naloxone formulations as standard emergency medications? CONCLUSIONS: The addictions treatment field has rushed prematurely into the use of improvised nasal naloxone kits. Evidence of adequate bioavailability and acceptable pharmacokinetic curves are vital preliminary steps, especially when effective approved formulations exist.

Strang, J., R. McDonald, et al. (2019). "Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine." Drugs 79(13): 1395-1418.

Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of 'take-home naloxone' has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use opioids as well as non-medical personnel), with the recommendation to administer the naloxone to the overdose victim as interim care while awaiting an ambulance. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than 100,000 deaths worldwide annually. Rises in mortality are particularly sharp in North America, where the ongoing prescription opioid problem is now overlaid with a rapid growth in overdose deaths from heroin and illicit fentanyl. Using opioids alone is dangerous, and the mortality risk is clustered at certain times and contexts, including on prison release and discharge from hospital and residential care. The provision of take-home naloxone has required the introduction of new legislation and new naloxone products. These include pre-filled syringes and auto-injectors and, crucially, new concentrated nasal sprays (four formulations recently approved in different countries) with speed of onset comparable to intramuscular naloxone and relative bioavailability of approximately 40-50%. Choosing the right naloxone dose in the fentanyl era is a matter of ongoing debate, but the safety margin of the approved nasal sprays is superior to improvised nasal kits. New legislation in different countries permits over-the-counter sales or other prescription-free methods of provision. However, access remains uneven with take-home naloxone still not provided in many countries and communities, and with ongoing barriers contributing to implementation inertia. Take-home naloxone is an important component of the response to the global overdose problem, but greater commitment to implementation will be essential, alongside improved affordable products, if a greater impact is to be achieved.

Tippey, K. G., M. Yovanoff, et al. (2019). "Comparative Human Factors Evaluation of Two Nasal Naloxone Administration Devices: NARCAN((R)) Nasal Spray and Naloxone Prefilled Syringe with Nasal Atomizer." Pain Ther 8(1): 89-98.

INTRODUCTION: Opioid overdose rescue situations are time-critical, high-stress scenarios that frequently require nonmedical first responders or bystanders to intervene and administer naloxone to avoid opioid-induced fatalities. Training nonmedical personnel to respond during such mentally constraining situations presents the human factors challenge of how best to design a safe and effective lay delivery system. This paper comparatively evaluates the ease of use of two nasal naloxone administration products: NARCAN((R)) Nasal Spray and a naloxone prefilled syringe with nasal atomizer (PFS-NA). METHODS: We evaluated the use requirements and usability of NARCAN((R)) Nasal Spray versus a naloxone PFS-NA using a systems-oriented method. First, we determined the use requirements of different user groups. Next, we focused on constructing a human factors task analysis of both products. Finally, we conducted a comparative risk assessment of the tasks that were different between the two products. RESULTS: Inexperienced users, such as nonmedical first responders and bystanders, are at the highest risk of incorrectly administering naloxone, particularly in high-stress emergency opioid overdose situations. The device Preparation and Medication Delivery tasks most differentiate the use of NARCAN((R)) Nasal Spray and a PFS-NA. The level of task complexity and number of steps within those tasks is substantially greater for a PFS-NA than for the NARCAN((R)) Nasal Spray. CONCLUSIONS: NARCAN((R)) Nasal Spray requires fewer steps and is easier to administer than a naloxone PFS-NA. Thus, using NARCAN((R)) Nasal Spray should increase the likelihood that nonmedical personnel correctly deliver naloxone in time-critical, high-stress opioid overdose rescue situations. FUNDING: ADAPT Pharma, Inc.

Unick GJ, Rosenblum D, Mars S, Ciccarone D (2013) Intertwined Epidemics: National Demographic Trends in Hospitalizations for Heroin- and Opioid-Related Overdoses, 1993–2009. PLoS ONE 8(2): e54496. doi:10.1371/journal.pone.0054496

The historical patterns of opiate use show that sources and methods of access greatly influence who is at risk. Today, there is evidence that an enormous increase in the availability of prescription opiates is fuelling a rise in addiction nationally, drawing in new initiates to these drugs and changing the geography of opiate overdoses. Recent efforts at supply-based reductions in prescription opiates may reduce harm, but addicted individuals may switch to other opiates such as heroin. In this analysis, we test the hypothesis that changes in the rates of Prescription Opiate Overdoses (POD) are correlated with changes in the rate of heroin overdoses (HOD). ICD9 codes from the Nationwide Inpatient Sample and population data from the Census were used to estimate overall and demographic specific rates of POD and HOD hospital admissions between 1993 and 2009. Regression models were used to test for linear trends and lagged negative binomial regression models were used to model the interrelationship between POD and HOD hospital admissions. Findings show that whites, women, and middle-aged individuals had the largest increase in POD and HOD rates over the study period and that HOD rates have increased in since 2007. The lagged models show that increases in a hospitals POD predict an increase in the subsequent years HOD admissions by a factor of 1.26 (p,0.001) and that each increase in HOD admissions increase the subsequent years POD by a factor of 1.57 (p,0.001). Our hypothesis of fungibility between prescription opiates and heroin was supported by these analyses. These findings suggest that focusing on supply-based interventions may simply lead to a shift in use to heroin rather minimizing the reduction in harm. The alternative approach of using drug abuse prevention resources on treatment and demand-side reduction is likely to be more productive at reducing opiate abuse related harm.

Valenzuela, T. D., E. W. Hook, 3rd, et al. (1985). "Occupational exposure to hepatitis B in paramedics." Arch Intern Med 145(11): 1976-7.

            To determine their occupational risk for hepatitis B infection, 59 Seattle paramedics were tested for hepatitis B serum markers. Evidence of antibody to hepatitis B surface antigen (anti-HBs) or antibody to hepatitis B core antigen (anti-HBc) was found in 25%, a rate five times that of a similar Seattle population. Seropositivity did not correlate with age, race, clinical history, or length of service. Of the 15 paramedics with seropositivity to hepatitis B virus six initially had low titers of either anti-HBs or anti-HBc. Four of the six demonstrated persistent low-grade seropositivity on retesting. Paramedics are at increased risk of hepatitis B infection. The high frequency of low-titer anti-HBs suggests that frequent low-level exposure to hepatitis B virus occurs in this population; hepatitis B vaccine should be strongly considered for paramedics.

Vanky, E., L. Hellmundt, et al. (2017). "Pharmacokinetics after a single dose of naloxone administered as a nasal spray in healthy volunteers." Acta Anaesthesiol Scand 61(6): 636-640.

            BACKGROUND: There is increasing interest in the use of intranasal naloxone to reverse adverse opioid effects during management of procedural pain in children and in adults after overdose. There are limited data on the pharmacokinetics of intranasal naloxone so in this study we aimed to detail the pharmacokinetic profile of the commercially marketed injectable solution of naloxone 0.4 mg/ml when administered as an intranasal spray. METHODS: Twenty healthy volunteers received naloxone as an intranasal spray at a dose of 10 mug/kg. Venous blood sampling was carried out for 90 min after administration to determine the time profile of the plasma concentrations of using tandem mass spectrometry. Pharmacokinetic parameters were calculated using a one-compartment model. RESULTS: Median time to maximum naloxone concentration (Tmax) was 14.5 (95% CI: 9.0-16.5) min, mean maximum naloxone concentration (Cmax) was 1.09 +/- 0.56 ng/ml and mean AUC0-90 min was 37.1 +/- 15.0 ng*min/ml. Elimination half-life estimated from the median concentration data was 28.2 min. CONCLUSION: Our results show a faster uptake of intranasal naloxone to maximum concentration compared with previous studies although with a marked variation in maximum concentration. The findings are consistent with our clinical experience of the time profile for reversing the effects of sufentanil sedation in children.

Vilke, G. M., J. Buchanan, et al. (1999). "Are heroin overdose deaths related to patient release after prehospital treatment with naloxone?" Prehosp Emerg Care 3(3): 183-6.

            OBJECTIVE: Naloxone is frequently used by prehospital care providers to treat suspected heroin and opioid overdoses. The authors' EMS system has operated a policy of allowing these patients, once successfully treated, to sign out against medical advice (AMA) in the field. This study was performed to evaluate the safety of this practice. METHODS: The authors retrospectively reviewed all 1996 San Diego County Medical Examiner's (ME's) cases in which opioid overdoses contributed to the cause of death. The records of all patients who were found dead in public or private residences or died in emergency departments of reasons other than natural causes or progression of disease, are forwarded to the ME office. ME cases associated with opiate use as a cause of death were cross-compared with all patients who received naloxone by field paramedics and then refused transport. The charts were reviewed by dates, times, age, sex, location, and, when available, ethnicity. RESULTS: There were 117 ME cases of opiate overdose deaths and 317 prehospital patients who received naloxone and refused further treatment. When compared by age, time, date, sex, location, and ethnicity, there was no case in which a patient was treated by paramedics with naloxone within 12 hours of being found dead of an opiate overdose. CONCLUSIONS: Giving naloxone to heroin overdoses in the field and then allowing the patients to sign out AMA resulted in no death in the one-year period studied. This study did not evaluate for return visits by paramedics nor whether patients were later taken to hospitals by private vehicles.

Wagner, K. D., P. J. Davidson, et al. (2014). ""I felt like a superhero": the experience of responding to drug overdose among individuals trained in overdose prevention." Int J Drug Policy 25(1): 157-165.

BACKGROUND: Overdose prevention programs (OPPs) train people who inject drugs and other community members to prevent, recognise and respond to opioid overdose. However, little is known about the experience of taking up the role of an "overdose responder" for the participants. METHODS: We present findings from qualitative interviews with 30 participants from two OPPs in Los Angeles, CA, USA from 2010 to 2011 who had responded to at least one overdose since being trained in overdose prevention and response. RESULTS: Being trained by an OPP and responding to overdoses had both positive and negative effects for trained "responders". Positive effects include an increased sense of control and confidence, feelings of heroism and pride, and a recognition and appreciation of one's expertise. Negative effects include a sense of burden, regret, fear, and anger, which sometimes led to cutting social ties, but might also be mitigated by the increased empowerment associated with the positive effects. CONCLUSION: Findings suggest that becoming an overdose responder can involve taking up a new social role that has positive effects, but also confers some stress that may require additional support. OPPs should provide flexible opportunities for social support to individuals making the transition to this new and critical social role. Equipping individuals with the skills, technology, and support they need to respond to drug overdose has the potential to confer both individual and community-wide benefits.

Wagner, K. D., T. W. Valente, et al. (2010). "Evaluation of an overdose prevention and response training programme for injection drug users in the Skid Row area of Los Angeles, CA." Int J Drug Policy 21(3): 186-193.

BACKGROUND: Fatal opioid overdose is a significant cause of mortality among injection drug users (IDUs). METHODS: We evaluated an overdose prevention and response training programme for IDUs run by a community-based organisation in Los Angeles, CA. During a 1-h training session participants learned skills to prevent, recognise, and respond to opioid overdoses, including: calling for emergency services, performing rescue breathing, and administering an intramuscular injection of naloxone (an opioid antagonist). Between September 2006 and January 2008, 93 IDUs were trained. Of those, 66 (71%) enrolled in the evaluation study and 47 participants (71%) completed an interview at baseline and 3-month follow-up. RESULTS: Twenty-one percent of participants were female, 42% were white, 29% African American, and 18% Latino. Most were homeless or lived in temporary accommodation (73%). We found significant increases in knowledge about overdose, in particular about the use of naloxone. Twenty-two participants responded to 35 overdoses during the follow-up period. Twenty-six overdose victims recovered, four died, and the outcome of five cases was unknown. Response techniques included: staying with the victim (85%), administering naloxone (80%), providing rescue breathing (66%), and calling emergency services (60%). The average number of appropriate response techniques used by participants increased significantly from baseline to follow-up (p<0.05). Half (53%) of programme participants reported decreased drug use at follow-up. CONCLUSION: Overdose prevention and response training programmes may be associated with improved overdose response behaviour, with few adverse consequences and some unforeseen benefits, such as reductions in personal drug use.

Walley, A. Y., M. Doe-Simkins, et al. (2012). "Opioid overdose prevention with intranasal naloxone among people who take methadone." J Subst Abuse Treat.

Overdose education and naloxone distribution (OEND) is an intervention that addresses overdose, but has not been studied among people who take methadone, a drug involved in increasing numbers of overdoses. This study describes the implementation of OEND among people taking methadone in the previous 30days in various settings in Massachusetts. From 2008 to 2010, 1553 participants received OEND who had taken methadone in the past 30days. Settings included inpatient detoxification (47%), HIV prevention programs (25%), methadone maintenance treatment programs (MMTP) (17%), and other settings (11%). Previous overdose, recent inpatient detoxification and incarceration, and polysubstance use were overdose risks factors common among all groups. Participants reported 92 overdose rescues. OEND programs are public health interventions that address overdose risk among people who take methadone and their social networks. OEND programs can be implemented in MMTPs, detoxification programs, and HIV prevention programs.

Wanger, K., L. Brough, et al. (1998). "Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose." Acad Emerg Med 5(4): 293-9.

            OBJECTIVE: To determine whether naloxone administered i.v. to out-of- hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (s.q.). METHODS: A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate > or =10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg i.v. (n = 74) or naloxone 0.8 mg s.q. (n = 122), for respiratory depression of or =10 breaths/min was 9.3 +/- 4.2 min for the i.v. group vs 9.6 +/- 4.58 min for the s.q. group (95% CI of the difference -1.55, 1.00). Mean duration of bag- valve-mask ventilation was 8.1 +/- 6.0 min for the i.v. group vs 9.1 +/- 4.8 min for the s.q. group. Cost of materials for administering naloxone 0.4 mg i.v. was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg s.q. CONCLUSION: There was no clinical difference in the time interval to respiratory rate > or =10 breaths/min between naloxone 0.8 mg s.q. and naloxone 0.4 mg i.v. for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the s.q. route was offset by the delay in establishing an i.v.

Weiner, S. G., P. M. Mitchell, et al. (2017). "Use of Intranasal Naloxone by Basic Life Support Providers." Prehosp Emerg Care 21(3): 322-326.

                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.

Wermeling, D. P. (2010). "Opioid harm reduction strategies: focus on expanded access to intranasal naloxone." Pharmacotherapy 30(7): 627-631.

Wermeling, D. P. (2015). "Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access." Ther Adv Drug Saf 6(1): 20-31.

Opioid overdose and mortality have increased at an alarming rate prompting new public health initiatives to reduce drug poisoning. One initiative is to expand access to the opioid antidote naloxone. Naloxone has a long history of safe and effective use by organized healthcare systems and providers in the treatment of opioid overdose by paramedics/emergency medicine technicians, emergency medicine physicians and anesthesiologists. The safety of naloxone in a prehospital setting administered by nonhealthcare professionals has not been formally established but will likely parallel medically supervised experiences. Naloxone dose and route of administration can produce variable intensity of potential adverse reactions and opioid withdrawal symptoms: intravenous administration and higher doses produce more adverse events and more severe withdrawal symptoms in those individuals who are opioid dependent. More serious adverse reactions after naloxone administration occur rarely and may be confounded by the effects of other co-intoxicants and the effects of prolonged hypoxia. One component of the new opioid harm reduction initiative is to expand naloxone access to high-risk individuals (addicts, abusers, or patients taking high-dose or extended-release opioids for pain) and their close family or household contacts. Patients or their close contacts receive a naloxone prescription to have the medication on their person or in the home for use during an emergency. Contacts are trained on overdose recognition, rescue breathing and administration of naloxone by intramuscular injection or nasal spraying of the injection prior to the arrival of emergency medical personnel. The safety profile of naloxone in traditional medical use must be considered in this new context of outpatient prescribing, dispensing and treatment of overdose prior to paramedic arrival. New naloxone delivery products are being developed for this prehospital application of naloxone in treatment of opioid overdose and prevention of opioid-induced mortality.

Williams, K., E. S. Lang, et al. (2019). "Evidence-Based Guidelines for EMS Administration of Naloxone." Prehosp Emerg Care 23(6): 749-763.

The opioid crisis is a growing concern for Americans, and it has become the leading cause of injury-related death in the United States. An adjunct to respiratory support that can reduce this high mortality rate is the administration of naloxone by Emergency Medical Services (EMS) practitioners for patients with suspected opioid overdose. However, clear evidence-based guidelines to direct EMS use of naloxone for opioid overdose have not been developed. Leveraging the recent Agency for Healthcare Research and Quality (AHRQ) systematic review on the EMS administration of naloxone for opioid poisonings, federal partners determined the need for a clinical practice guideline for EMS practitioners faced with suspected opioid poisoning. Project funding was provided by the National Highway Traffic Safety Administration, Office of EMS, (NHTSA OEMS), and the Health Resources and Services Administration, Maternal and Child Health Bureau's EMS for Children Program (EMSC). The objectives of this project were to develop and disseminate an evidence-based guideline and model protocol for administration of naloxone by EMS practitioners to persons with suspected opioid overdose. We have four recommendations relating to route of administration, all conditional, and all supported by low or very low certainty of evidence. We recommend the intravenous route of administration to facilitate titration of dose, and disfavor the intramuscular route due to difficulty with titration, slower time to clinical effect, and potential exposure to needles. We equally recommend the intranasal and intravenous routes of administration, while noting there are variables which will determine which route is best for each patient. Where we are unable to make recommendations due to evidence limitations (dosing, titration, timing, and transport) we offer technical remarks. Limitations of our work include the introduction of novel synthetic opioids after many of the reviewed papers were produced, which may affect the dose of naloxone required for effect, high risk of bias and imprecision in the reviewed papers, and the introduction of new naloxone administration devices since many of the reviewed papers were published. Future research should be conducted to evaluate new devices and address the introduction of synthetic opioids.

Wolfe, T. R. and E. D. Barton (2003). "Reducing needlestick risk: Nasal drug delivery in EMS." J Emerg Med Serv JEMS 28(12): 52-63.

Wu, C., T. Brown, et al. (2019). "Access to naloxone at community pharmacies under the Massachusetts statewide standing order." J Am Pharm Assoc (2003).

OBJECTIVE: This study aimed to evaluate access to, and barriers to accessing, naloxone at community pharmacies throughout Massachusetts following implementation of new legislation that requires all community pharmacies to maintain a sufficient supply for dispensing under a statewide standing order. DESIGN: From September 2018 through January 2019, we conducted a cross-sectional telephone-based survey of Massachusetts pharmacies by having an interviewer pose as a customer seeking naloxone. SETTING AND PARTICIPANTS: Community pharmacies were identified from a list of all actively licensed pharmacies provided by the Massachusetts Department of Public Health and one-half were randomly selected for inclusion. Pharmacies that were permanently closed, duplicated on the list, or closed to the general public were excluded from analysis. OUTCOME MEASURES: Rates of stocked naloxone, perceived need for identification or prescription, and pricing. RESULTS: Of the 524 pharmacies surveyed, 97.7% (n = 512) reported routinely stocking naloxone. Of those, 90.4% (n = 463) had naloxone in stock on the day of contact. Most pharmacies with naloxone in stock did not require a prescription (96.1%; n = 445); at these pharmacies, personal identification was required by 38.9% (n = 180). The average out-of-pocket naloxone nasal spray price was $128.34 +/- $40.75. CONCLUSION: Nearly all Massachusetts community pharmacies routinely stock naloxone as required by state law; however, barriers remain regarding perceived need for identification and high out-of-pocket costs.