Open Access Emergency Medicine
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`Assessment of the safety and ease of use
`of the naloxone auto-injector for the reversal
`of opioid overdose
`
`Mark A Merlin1,2
`Navin Ariyaprakai1
`Faizan H Arshad1,2
`1Newark Beth israel Medical Center,
`Newark, NJ, USA; 2Monmouth Ocean
`Hospital Service Corporation (MONOC),
`wall Township, NJ, USA
`
`Correspondence: Mark A Merlin
`Newark Beth israel Medical Center,
`201 Lyons Avenue D-11, Newark,
`NJ, USA
`Email markamerlin@gmail.com
`
`submit your manuscript | www.dovepress.com
`Dovepress
`http://dx.doi.org/10.2147/OAEM.S82133
`
`Abstract: Over the last decade, opioid-related deaths in the United States have increased at
`an alarming rate. The use of naloxone by laypersons is a newer concept and its utilization can
`benefit patients by rapid administration due to it being readily available immediately after an
`opioid overdose. The US Food and Drug Administration approved a naloxone auto-injector on
`April 3, 2014 for adults and pediatrics, designed for use by anyone including patients, family
`members, bystanders, and medical professionals. This device (EZVIO™) is the first device of its
`kind available on the market. The auto-injector is a battery-operated disposable 0.4 mg/0.4 mL
`prefilled device for use in the lateral thigh by patients, bystanders, or health care professionals.
`It utilizes auditory and visual commands for ease of administration and instructs patients to
`seek further medical care after injection. EVZIO costs about $600 for two auto-injectors and
`a trainer. Additionally, in August 2013, the Substance Abuse and Mental Health Services
`Administration introduced the Opioid Overdose Toolkit, a federal resource promoting safety
`and prevention information. This extensive document provides information for medical profes-
`sionals, first responders, patients, caregivers, and overdose survivors. It outlines many strategies
`for dealing with this health care crisis. Most importantly, it highlights the importance of rapid
`recognition and treatment of opioid overdoses as well as routine conversations with patients
`assessing the need for naloxone prescriptions. The auto-injector is a safe, portable device with
`limited instruction needed and should routinely be made available to anyone who has contact
`with an opioid user.
`Keywords: narcotics, abuse, heroin, EZVIO
`
`Introduction
`Opioid overdoses have become an international health crisis.1 Over the last decade,
`opioid-related deaths in the United States have increased at an alarming rate. There
`were more than four-times as many opioid fatalities in 2011 than there were in 1999.2
`Center for Disease Control data for the US demonstrates the age-adjusted rate for
`opioid-analgesic poisoning deaths went from 1.4 per 100,000 in 1999 to 5.4 per 100,000
`in 2011.2 In 2012, there were 16,007 deaths due to opioids and 5,925 due to heroin in
`the US, which equates to two deaths per hour.3
`Naloxone hydrochloride is a short-acting, non-addictive, opioid antagonist that
`is used for respiratory or central nervous system depression from opioid overdose.4
`In 1971, naloxone received US Food and Drug Administration (FDA) approval.
` Subsequently, it has become the standard first-line agent in the emergency setting for
`rapid reversal of accidental or intentional opioid overdose.
`Previously, naloxone products were only available in glass vials and ampules. They
`are distributed with syringes and needles for manual injection, or with syringes and
`
`21
`Open Access Emergency Medicine 2015:7 21–24
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`Merlin et al
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`atomizers for nasal administration. Nasal administration is
`not FDA approved but is frequently utilized by emergency
`personnel. Use of naloxone by trained medical professionals
`requires minimal additional training and has been the stan-
`dard of care for opioid overdoses. However, the use of nalox-
`one by laypersons is a newer concept and its utilization can
`benefit patients by rapid administration due to it being readily
`available immediately after an opioid overdose. Subsequently,
`new and improved ways to provide the general public with
`the ability to utilize naloxone are being sought.
`This article reviews the current literature on a new, novel
`auto-injector available for patients. The review consists of
`available website and published literature on Medline from
`1966 to the present with a cross-reference of one paper from
`1963. Search terms utilized were “naloxone”, “auto-injector”,
`“opioid”, “overdose”, and “EZVIO”.
`
`New auto-injector
`The FDA approved a naloxone auto-injector on April 3, 2014
`for adults and pediatrics, designed for use by anyone includ-
`ing patients, family members, bystanders, and medical pro-
`fessionals. This device (EZVIO™; Kaleo Pharma, Richmond,
`VA, USA) is the first device of its kind available on the mar-
`ket. FDA Commissioner Margaret Hamburg called EVZIO
`“an extremely important innovation”.7 Dr Hamburg noted
`that EVZIO received its approval almost 10 weeks ahead of
`schedule.7 EVZIO labeling expands the scope of possible
`prescription recipients to caregivers, which is unusual for
`an FDA recommendation. Prescribers are encouraged to
`provide EVZIO to caregivers and others who are likely to
`witness and reverse an overdose without any professional
`supervision.
`The auto-injector is a battery-operated disposable
`0.4 mg/0.4 mL prefilled device for use in the lateral thigh by
`patients, bystanders or health care professionals which may
`be injected through clothing if necessary. It is supplied as a
`two-dose pack with an additional trainer. It utilizes auditory
`and visual commands for ease of administration and instructs
`patients to seek further medical care after injection. The device
`has a protective outer case that is approximately 7.5×5 cm
`and is stored at room temperature with an acceptable excur-
`sion range between 4°C and 40°C. The needle is a retractable
`23 gauge which is not visible during the entire injection
` process. Because of EVZIO small size, it is easy portable.
`A trainer device as well as visual and auditory instructions
`for use when activated is provided in each packet.5 The FDA
`accepted prior epinephrine auto-injector studies to demonstrate
`the safety and efficacy of the naloxone auto-injector.6,7
`
`The FDA required a human factor validation study for
`approval.8 Subjects consisted of 40 English-speaking partici-
`pants who were asked to use the device without training or
`reading the guide. The 40 participants consisted of 21 adults
`and 19 children (aged 12–19 years). Ten percent of partici-
`pants were unable to adequately deliver the medication to the
`patient. After analyzing the results, the FDA determined that
`a person could adequately utilize the device and fast-tracked
`approval. Approval was based on this study,8 but no safety
`or efficacy studies were required by the FDA. No human
`factor studies have been conducted in non-English-speaking
`individuals.
`
`Cost
`EVZIO costs about $600 for two auto-injectors and a trainer.
`Private insurers are currently considering payments. Patient
`assistance programs are available via Kaleo Pharmaceuticals
`(http://www.evzio.com).
`
`Access
`Typically throughout the US, prehospital advanced life sup-
`port personnel provide naloxone to a patient overdosing on
`opioids, most commonly heroin. However, depending on
`the region, some basic life support providers (emergency
`medical technicians) are unable to provide the medication.
`This depends on regional regulations. Davis et al conducted a
`national systematic legal review regarding emergency medi-
`cal services’ naloxone access.9 They evaluated all 50 states
`as well as the District of Columbia, Guam, and Puerto Rico
`in 2013. All 53 jurisdictions permit paramedics to administer
`naloxone. Of the 48 jurisdictions with intermediate-level
`emergency medical services personnel, all but one autho-
`rize naloxone administration. Twelve jurisdictions allow
`emergency medical technicians to administer naloxone and
`two permit general first responders to administer naloxone.
`This outlines the importance of maintaining the ability for
`laypersons to inject naloxone since responding ambulances
`in many jurisdictions will not have this medication. The time
`delay in medication administration can result in death or
`anoxic brain injury which may lead to permanent disability.
`Administration delivery time is the rate-limiting step in an
`opioid overdose.
`
`Naloxone distribution
`to the general public
`In 1996, several systems around the country began distribut-
`ing naloxone to nonmedical professionals with promising
`results. A program in Chicago was established in 1999 and
`
`22
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`Naloxone auto-injector in overdose
`
`later in New York City in 2005.10 These programs require that
`participants recognize an opioid overdose, assemble medica-
`tion, and administer medication.11 The time and materials for
`education differ depending on the program.12 The delivery
`of medication can range from intramuscular (IM) to subcu-
`taneous or intranasal. All modalities were generally similar
`in effectiveness.13–15
`In the United Kingdom, the N-ALIVE trial is provid-
`ing naloxone to recently released prisoners who are at the
`highest risk for opioid overdose with IM medication.16 The
`Staying Alive Overdose Prevention Project in Baltimore,
`MD utilized a 1-hour training session where participants
`learned rescue breathing, overdose recognition, and IM
`medication administration. They found that participants
`were able to recognize and treat an opioid overdose effec-
`tively, using IM naloxone.17 In a San Francisco program,
`patients received 5–10 minutes of education then demon-
`strated adequate recognition and ability to treat an over-
`dose.18 They believed that their community has a high base
`knowledge of opioid overdose. EVZIO also eliminates any
`assembly required in naloxone’s existing IM or off-label
`intranasal devices.
`
`Changes in heroin patterns
`by naloxone availability
`Heroin users do not increase their dose because naloxone is
`available. They do not want to experience withdrawal precipi-
`tated by naloxone.19 In one naloxone program for heroin users,
`the frequency of heroin injection and number of overdoses
`decreased.20 In communities where naloxone-distribution
`programs exist, opioid overdose deaths decrease.21,22 Addi-
`tionally, there is a perceived medical liability risk among
`health care providers to prescribe naloxone to third parties.
`Currently, one-third of states have victim shield laws protect-
`ing health care providers. With the FDA recommendation
`to prescribe to third parties, this may alleviate some fear
`among providers.
`
`Public awareness of opioid crisis
`Public awareness has increased with the aforementioned pro-
`grams and layperson distribution of naloxone. Additionally,
`in August 2013, the Substance Abuse and Mental Health
`Services Administration introduced the Opioid Overdose
`Toolkit (http://evzio.com/hcp/about-naloxone/samhsa-
`opioid-overdose-toolkit.php), a federal resource promoting
`safety and prevention information.23,24 This extensive docu-
`ment provides information for medical professionals, first
`responders, patients, caregivers, and overdose survivors.
`
`It outlines many strategies for dealing with this health
`care crisis. Most importantly, it highlights the importance
`of rapid recognition and treatment of opioid overdoses as
`well as routine conversations with patients in assessing the
`need for naloxone prescriptions. Ultimately, primary care
`providers need to complete a thorough social history to
`determine the need for a naloxone prescription.
`
`Risk of patient injection
`After administration of naloxone, participants are often
`instructed to seek further medical care depending on the regional
`program. In Copenhagen, Denmark, medical emergency care
`units staffed by physicians have been discharging selected
`patients on-scene after naloxone administration since 1994 with
`low risk of death due to rebound toxicity.25 In San Antonio, TX,
`USA, 592 patients were treated by paramedics with naloxone
`and then refused transport; none were found to have died within
`48 hours.26 In San Diego, CA, USA, 998 patients were treated by
`paramedics then signed against medical advice with no deaths
`from those patients in the next 12 hours.27
`
`Conclusion
`Opioid abuse has become endemic. The widespread abuse
`of opioid medications requires society to have a proactive
`response. The naloxone auto-injector is the first naloxone
`product designed for use by laypersons in the emergency
`treatment of known or suspected opioid overdose. The newly
`approved naloxone auto-injector is easy to use, requires
`little to no training, and is effective. Rapid dissemination of
`naloxone is the only effective means to combat the crisis of
`opioid overdose throughout the world. The auto-injector is
`a safe, portable device with limited instruction needed and
`should routinely be made available to anyone who has contact
`with an opioid user.
`
`Disclosure
`The authors report no conflicts of interest in this work.
`
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