Application of human factors engineering (HFE) to the design of a naloxone auto-injector for the treatment of opioid emergencies.

The increased use of opioids for chronic treatment of pain and the resulting epidemic of opioid overdoses have created a major public health challenge. Parenteral naloxone has been used since the 1970's to treat opioid overdose. Recently, a novel naloxone auto-injector device (EVZIO, kaleo, Inc., Richmond, VA) was approved by the Food and Drug Administration. In this article, we review the Human Factors Engineering (HFE) process used in the development and testing of this novel naloxone auto-injector currently used in nonmedical settings for the emergency treatment of known or suspected opioid overdose. HFE methods were employed throughout the product development process for the naloxone auto-injector including formative and summative studies in order to optimize the auto-injector's user interface, mitigate use-related hazards and increase reliability during an opioid emergency use scenario. HFE was also used to optimize the product's design and user interface in order to reduce or prevent user confusion and misuse. The naloxone auto-injector went through a rigorous HFE process that included perceptual, cognitive, and physical action analysis; formative usability evaluations; use error analysis and summative design validation studies. Applying HFE resulted in the development of a product that is safe, fast, easy and predictably reliable to deliver a potentially life-saving dose of naloxone during an opioid overdose emergency. The naloxone auto-injector may be considered as a universal precaution option for at-risk patients prescribed opioids or those who are at increased risk for an opioid overdose emergency.

Take-home naloxone treatment for opioid emergencies: a comparison of routes of administration and associated delivery systems.

INTRODUCTION: Naloxone reversal of opioid-induced respiratory depression outside of medical facilities has become more prevalent because of the escalating opioid epidemic in the USA. Take-home naloxone for treatment of opioid emergencies is now being recommended by numerous federal, state, and professional organizations. Areas covered: The scope of the opioid overdose epidemic is reviewed along with practical, clinical, regulatory, and usability considerations for take-home naloxone routes of administration currently available and associated delivery systems. Specific opioid-related factors are discussed in detail with emphasis placed on life-threatening respiratory depression and naloxone antagonism. A clinical overview, including pharmacokinetic and FDA approval information for each take-home naloxone product is discussed in detail as well as the impact of take-home naloxone in the community. Finally, given these products are to be used in a panic-stricken, life-threatening opioid emergency, an analysis of available usability data is provided with proposed directions for further study. Expert opinion: Based on the available clinical evidence, auto-injectable naloxone should be the preferred administration route for take-home naloxone treatment until additional safety, efficacy, and comparative outcomes data are available for unconventional routes of administration that unequivocally provide equal or superior results.

Patient Characteristics and Outcomes in Unintentional, Non-fatal Prescription Opioid Overdoses: A Systematic Review.

BACKGROUND: Opioid overdose continues to be a significant and growing cause of preventable mortality and morbidity. Studies suggest that unintentional, non-fatal overdose from prescription opioid analgesics constitutes a large portion of total overdose events. The societal burden associated with these events is a frequently overlooked public health concern. OBJECTIVES: To evaluate unintentional, non-fatal prescription opioid overdoses, including the identification of risk factors, societal burden, and knowledge gaps where further study is warranted. STUDY DESIGN: Systematic review of the literature for unintentional, non-fatal opioid overdose. METHODS: Preferred reporting items for systematic reviews and meta-analyses guidelines were used in constructing this systematic review. To determine the scope of the existing literature, a systematic search was conducted using the MEDLINE, CINAHL, PsycINFO, and Web of Science databases. RESULTS: This systematic review analyzes 24 articles (21 retrospective descriptive analyses, 2 prospective analyses, one phase III trial, and one meta-analysis). Articles were reviewed by authors and relevant data examined. Results show that opioid overdose morbidity is significantly more prevalent than mortality and sequelae of non-fatal events should be studied in more detail. LIMITATIONS: The limitations of this systematic review include the range of study populations and opioids discussed and the broad and variable definitions of "opioid overdose" in the literature. CONCLUSIONS: Opioid overdose morbidity and mortality is seen across the entire spectrum of inpatient and outpatient use with significant numbers of adverse events occurring in population segments not identified by high risk indicators. Increased physician awareness and a multi-modal approach could help mitigate the overdose epidemic while maintaining effective pain control for patients. KEY WORDS: Prescription, opioid, accidental drug overdose, unintentional overdose, drug poisoning, fentanyl, oxycodone, hydrocodone, methadone, oxymorphone, hydromorphone.

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery.

INTRODUCTION: The standard of care for reversal of opioid-induced respiratory depression associated with opioid overdose is injectable naloxone. This study compared the usability of two naloxone delivery devices, a naloxone auto-injector (NAI) and a naloxone intranasal delivery system (NXN), in the administration of naloxone during a simulated opioid overdose emergency. NAI (EVZIO (®) ; kaleo, Inc., Richmond, VA, USA) is a Food and Drug Administration approved single-use pre-filled auto-injector containing 0.4 mg of naloxone. METHODS: Study participants were randomly assigned to administer naloxone using NAI and NXN, sequentially. The primary endpoint was successful administration of a simulated dose of naloxone into a mannequin during a simulated opioid emergency, both before and after receiving training. Secondary endpoints included using the NAI or NXN in accordance with the instructions-for-use and the comparative measurement of successful completion time of administration for both NAI and NXN. RESULTS: A total of 42 healthy participants aged 18-65 years were enrolled in the study. The proportion of participants able to successfully administer a simulated dose of naloxone was significantly greater for NAI compared to NXN both before (90.5% vs. 0.0%, respectively, P < 0.0001) and after (100% vs. 57.1%, respectively, P < 0.0001) participant training. The proportion of participants able to administer a simulated dose of naloxone in accordance with the instructions-for-use was also significantly greater for NAI compared to NXN before (85.7% vs. 0.0%, respectively, P < 0.0001) and after (100% vs. 0.0%, respectively, P < 0.0001) participant training. The average time to task completion for administration attempt before training was 0.9 ± 0.25 min for NAI versus 6.0 ± 4.76 min for NXN and after training was 0.5 ± 0.15 min for NAI versus 2.0 ± 2.15 min for NXN. CONCLUSION: Laypersons experienced substantially greater success administering a simulated dose of naloxone, both before and after training, using NAI versus NXN during a simulated opioid overdose emergency. No participants correctly used NXN without training.

Drug-device combination products in the twenty-first century: epinephrine auto-injector development using human factors engineering.

INTRODUCTION: The systematic application of human factors engineering (HFE) principles to the development of drug-device combination products, including epinephrine auto-injectors (EAIs), has the potential to improve the effectiveness and safety of drug administration. AREAS COVERED: A PubMed search was performed to assess the role of HFE in the development of drug-device combination products. The following keywords were used in different combinations: 'human factors engineering,' 'human factors,' 'medical products,' 'epinephrine/adrenaline auto-injector,' 'healthcare' and 'patient safety.' This review provides a summary of HFE principles and their application to the development of drug-device combination products as advised by the US FDA. It also describes the HFE process that was applied to the development of Auvi-Q, a novel EAI, highlighting specific steps that occurred during the product-development program. EXPERT OPINION: For drug-device combination products, device labeling and usability are critical and have the potential to impact clinical outcomes. Application of HFE principles to the development of drug-delivery devices has the potential to improve product quality and reliability, reduce risk and improve patient safety when applied early in the development process. Additional clinical and real-world studies will confirm whether the application of HFE has helped to develop an EAI that better meets the needs of patients at risk of anaphylaxis.

Bioavailability of epinephrine from Auvi-Q compared with EpiPen.

BACKGROUND: Epinephrine autoinjectors are underused for the treatment of anaphylaxis in community settings. Auvi-Q, a novel epinephrine autoinjector, was designed to be intuitive to use and reduce the potential for use-related errors. OBJECTIVE: To compare the bioavailability of 0.3 mg of epinephrine (adrenaline) injected with Auvi-Q and EpiPen in healthy adults. METHODS: In this randomized, single-blind, 2-treatment, 3-period, 3-sequence crossover study, healthy adults (18-45 years old) received a single injection of 0.3 mg of epinephrine with Auvi-Q in one period and with EpiPen in the other 2 periods. Blood samples were obtained before and 14 times during 6 hours after the dose. Outcomes included peak plasma concentration (Cmax), total epinephrine exposure (area under the concentration-time curve [AUC] from baseline to the last measurable concentration [AUC0-t] and extrapolated to infinity [AUCinf]), and adverse events. RESULTS: Seventy-one volunteers (53 male, 74.6%), with a mean age of 33.2 years and a mean body mass index of 25.4, were randomized. Epinephrine peak concentration and total exposure were similar between Auvi-Q (Cmax = 0.486 ng/mL; AUC0-t = 0.536 ng·h/mL; AUCinf = 0.724 ng·h/mL) and EpiPen (Cmax = 0.520 ng/mL; AUC0-t = 0.466 ng·h/mL; AUCinf = 0.583 ng·h/mL). Cmax and AUC analyses demonstrated bioequivalence between Auvi-Q and EpiPen. Most treatment-emergent adverse events were mild (98%), and all resolved spontaneously. Rates of injection-site pain and bleeding were 13% and 5%, respectively, for Auvi-Q vs 24% and 10%, respectively, for EpiPen. CONCLUSION: After a single injection of 0.3 mg of epinephrine, Auvi-Q and EpiPen had similar peak and total epinephrine exposure, were bioequivalent, and had similar safety profiles.

Design validation and labeling comprehension study for a new epinephrine autoinjector.

BACKGROUND: To facilitate the correct use of epinephrine autoinjectors (EAIs) by patients and caregivers, a novel EAI (Auvi-Q) was designed to help minimize use-related hazards. OBJECTIVE: To support validation of Auvi-Q final design and assess whether the instructions for use in the patient information leaflet (PIL) are effective in training participants on proper use of Auvi-Q. METHODS: Healthy participants, 20 adult and 20 pediatric, were assessed for their ability to complete a simulated injection by following the Auvi-Q instructions for use. Participants relied only on the contents of the PIL and other labeling features (device labeling and its instructions for use, electronic voice instructions and visual prompts). RESULTS: The mean ± SD age of the adult and pediatric participants was 39.4 ± 11.6 and 10.9 ± 2.3 years, respectively. In total, 80% of adult and 35% of pediatric participants had prior experience with EAIs. All adults and 95% of pediatric participants completed a simulated injection on the first attempt; 1 pediatric participant required parental training and a second attempt. Three adult and 4 pediatric participants exhibited a noncritical issue while successfully completing the simulated injection. Most participants agreed that the injection steps were easy to follow and the PIL facilitated understanding on using Auvi-Q safely and effectively. CONCLUSION: The PIL and other labeling features were effective in communicating instructions for successful use of Auvi-Q. This study provided validation support for the final design and anticipated instructions for use of Auvi-Q.

Voluntarily reported unintentional injections from epinephrine auto-injectors.

BACKGROUND: Epinephrine auto-injectors provide life-saving prehospital treatment for individuals experiencing anaphylaxis in community settings. OBJECTIVE: To determine the number, demographics, and associated circumstances and outcomes of unintentional injections from epinephrine auto-injectors. METHODS: We searched the databases of the American Association of Poison Control Centers and the Food and Drug Administration's Safety Information and Adverse Event Report System for these incidents as reported by members of the public and by health care professionals. RESULTS: From 1994 to 2007, a total of 15,190 unintentional injections from epinephrine auto-injectors were reported to US Poison Control Centers, 60% of them from 2003 to 2007. Those unintentionally injected had a median age of 14 years (interquartile range, 8-35), 55% were female, and 85% were injected in a home or other residence. Management was documented in only 4101 cases (27%), of whom 53% were observed without intervention, 29% were treated, 13% were neither held for observation nor treated, and 4% refused treatment. In contrast, from 1969 to 2007, only 105 unintentional injections from epinephrine auto-injectors were reported to MedWatch. Forty percent of these occurred during attempts to treat allergic reactions. Injuries resulting in permanent sequelae were rarely reported to either US Poison Control Centers or to MedWatch. CONCLUSION: The number of reported unintentional injections from epinephrine auto-injectors increased annually from 1994 to 2007. To prevent these unintentional injections, improved epinephrine auto-injector design is needed, along with increased vigilance in training the trainers and in training and coaching the users, as well as efforts to increase public awareness of the role of epinephrine auto-injectors in the first-aid treatment of anaphylaxis in the community.

Hazards of unintentional injection of epinephrine from autoinjectors: a systematic review.

OBJECTIVES: To ascertain the rate of occurrence of unintentional injections from epinephrine autoinjectors used in the first aid treatment of anaphylaxis and to provide information about the resulting needle stick injuries. DATA SOURCES: A systematic review was performed. The MEDLINE, Scirus, CINAHL, ISI Web of Science, and Google Scholar databases were searched by title and abstract to identify reports of unintentional injections from epinephrine autoinjectors published in peer-reviewed journals. STUDY SELECTION: Publications were selected for inclusion based on predefined strict criteria. RESULTS: In 26 reports published during the past 20 years, we identified 69 people with an unintentional injection of epinephrine from an autoinjector. More than 68% of them were reported in the past 6.3 years, 58% were female, 42% were injured in the home, and 91% sustained injury to a finger or thumb. More than 65% of the 69 individuals were evaluated in an emergency department; 13% of the 69 were not treated or were treated only with observation. Warming of the injured part was used in 25%, nitroglycerin paste application in 9%, local injections of phentolamine and/or lidocaine in 22%, and other treatments in 20%; treatment, or lack thereof, was not described in 12%. No permanent sequelae were reported. CONCLUSIONS: The true rate of occurrence of unintentional injection of epinephrine from autoinjectors is unknown but is increasing. People at risk for anaphylaxis need regular coaching in how to use epinephrine autoinjectors correctly and safely. Improved autoinjector design will address the safety concerns identified in this review.