Prehospital Emergency Care
`
`ISSN: 1090-3127 (Print) 1545-0066 (Online) Journal homepage: http://www.tandfonline.com/loi/ipec20
`
`Pitfalls of Intranasal Naloxone
`
`Matthew Zuckerman MD, Stacy N. Weisberg MPH, MD, FACEP & Edward W.
`Boyer MD, PhD, FACEP
`
`To cite this article: Matthew Zuckerman MD, Stacy N. Weisberg MPH, MD, FACEP & Edward W.
`Boyer MD, PhD, FACEP (2014) Pitfalls of Intranasal Naloxone, Prehospital Emergency Care, 18:4,
`550-554, DOI: 10.3109/10903127.2014.896961
`To link to this article: http://dx.doi.org/10.3109/10903127.2014.896961
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`Published online: 15 May 2014.
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`CASECONFERENCES
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`PITFALLSOF INTRANASALNALOXONE
`Matthew Zuckerman, MD, Stacy N. Weisberg, MPH, MD, FACEP,
`Edward W. Boyer, MD, PhD, FACEP
`
`largely by region, the overall trend is ever increasing
`with some areas showing a 500% increase from 2000 to
`2010.3 As prescriptions for opioids increase, nonmedi-
`cal use and opioid-related death also increase.4
`Public health policy experts respond to this epidemic
`by calling for primary prevention that monitors for
`doctor shopping,
`statewide prescription monitoring
`programs, and prescribing guidelines to curtail the
`inappropriate use of opioid medications. Meanwhile,
`secondary prevention has focused on naloxone as a
`means of reducing the morbidity and mortality asso-
`ciated with nonmedical use of opioids. Initial studies
`focused on use of intramuscular naloxone to prevent
`death from heroin abuse.5,6 More recently intranasal
`naloxone has become available and more attractive to
`both prehospital providers and nonmedical person-
`nel. The initial benefit of intranasal administration of
`naloxone appeared to be ease of use by nonmedical
`providers. Due to concerns over delays in achieving
`intravenous access and reducing body fluid exposure,
`some EMS (emergency medical services) systems have
`started utilizing intranasal naloxone as first-line ther-
`apy for opioid overdose.7,8 While intranasal naloxone
`has allowed for needle-less bystander opioid overdose
`rescue, issues regarding bioavailability, titratability, ef-
`fectiveness in cases of nonheroin overdose, and ulti-
`mately whether this delivery method is appropriate for
`first-line EMS response remain unclear. As with any
`therapeutic intervention, previously published case re-
`ports highlight successful use of intranasal naloxone,
`but reporting bias may lead to an underestimation of
`treatment failures. We present a case where intranasal
`(IN) naloxone failed to achieve the desired effect of im-
`proved ventilation, requiring the administration of in-
`travenous (IV) naloxone.
`CASE
`The patient was a 26-year-old male with history of
`opioid abuse who was found with agonal respira-
`tions, decreased mental status, and miotic pupils
`after intentionally masticating two 25- g fentanyl
`
`ABSTRACT
`We present a case of failed prehospital treatment of fentanyl
`induced apnea with intranasal (IN) naloxone. While IN ad-
`ministration of naloxone is becoming more common in both
`lay and pre-hospital settings, older EMS protocols utilized
`intravenous (IV) administration. Longer-acting, higher po-
`tency opioids, such as fentanyl, may not be as easily reversed
`as heroin, and studies evaluating IN administration in this
`population are lacking. In order to contribute to our under-
`standing of the strengths and limitations of IN administra-
`tion of naloxone, we present a case where it failed to restore
`ventilation. We also describe peer reviewed literature that
`supports the use of IV naloxone following heroin overdose
`and explore possible limitations of generalizing this litera-
`ture to opioids other than heroin and to IN routes of ad-
`ministration. Key words:
`prescription opioids, overdose,
`intranasal naloxone
`PREHOSPITALEMERGENCYCARE2014;18:550554
`
`INTRODUCTION
`Every 14 minutes another young adult dies from drug
`overdose in the United States.1 Closer inspection re-
`veals that opioid analgesics are driving this epidemic.2
`Over half of drug overdose deaths involve prescription
`pharmaceuticals, and opioid analgesics are involved
`in approximately 3 of every 4 pharmaceutical over-
`dose deaths. Though prescription of opioids varies
`
`Downloaded by [NIH Library] at 14:40 15 March 2016
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`Received November 8, 2013 from the Department of Emergency
`Medicine, University of Massachusetts Medical School, Worcester,
`Massachusetts. Revision received January 14, 2014; accepted for pub-
`lication February 4, 2014.
`The authors report no conflicts of interest. The authors alone are re-
`sponsible for the content and writing of the paper.
`Address correspondence to Stacy N. Weisberg, MPH, MD, FACEP,
`Department of Emergency Medicine, University of Massachusetts
`Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
`e-mail: Stacy.Weisberg@umassmemorial.org
`doi: 10.3109/10903127.2014.896961
`
`550
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`M. Zuckermanet al. PITFALLSOF INTRANASALNALOXONE
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`patches. He was found by his wife who called 9-1-1.
`Paramedics noted that the patient had heart rate of
`56 beats per minute, respiratory rate of 6 breaths per
`minute, and pulse oximetry of 89% with clammy skin.
`Paramedics recognized a possible opiate overdose and
`administered 1 mg naloxone atomizer in each nostril
`with no change in respiratory rate over the subsequent
`11 minutes. Paramedics then placed a peripheral IV
`line and administered naloxone 1 mg intravenously;
`this resulted in the desired endpoint of normalization
`of respirations and improvement in mental status.
`Following administration of intravenous naloxone,
`the patient was tremulous and nauseated. Upon
`arrival
`in the emergency department, the patient
`had a respiratory rate of 20, oxygen saturation of
`94% on 100% O2 via nonrebreather, pulse 150 beats
`per minute, blood pressure 176/151 mmHg, and oral
`temperature of 35.8 C. The patient at this time also had
`5-mm reactive pupils bilaterally. Within 15 minutes of
`arrival, however, the patient required two additional
`doses of naloxone 0.4 mg IV. Serum ethanol level
`upon admission was undetectable. Urine toxicology
`via GCMS was positive for nicotine and metabolytes,
`caffeine, fentanyl and metabolytes, chlorpheniramine,
`and citalopram. The patient was observed overnight
`on a cardiopulmonary monitor for recurrence of apnea
`or hypoventilation, but did not require any further
`administration of naloxone.
`DISCUSSION
`This case highlights the potential pitfalls of using in-
`tranasal naloxone for rescue in an undifferentiated opi-
`oid overdose. Naloxone has previously been adminis-
`
`551
`
`tered parenterally in medical settings to reverse heroin
`overdose. More recently, take-home naloxone (THN)
`programs utilizing bystander IN naloxone along with
`intensive overdose education campaigns have been as-
`sociated with decreased mortality from overdose in
`particular populations.9 Such studies are limited by
`a lack of reporting on individual cases and a study
`design that often classifies all administrations as life
`saved, potentially minimizing unsuccessful adminis-
`trations and adverse outcomes. At the same time, uti-
`lization of IN naloxone by EMS provides more detailed
`reporting. This may include important information on
`vital signs and physical exam gathered by trained
`medical staff, as well as documentation that may in-
`dicate whether IN naloxone was successful. Before im-
`plementing widespread use of EMS-administered IN
`naloxone, it is important to understand if prior studies
`that focused on heroin overdose are generalizable to
`patients abusing other agents, as well as whether stud-
`ies focusing on bystander intervention are generaliz-
`able to paramedics.
`During much of the twentieth century, naloxone was
`administered largely in response to heroin overdose;
`this pattern has changed as opioid related deaths are
`five times as likely to be due to prescription opioid
`analgesics rather than heroin.10 Data from the Drug
`Abuse Warning Network suggests that nonmedical use
`of oxycodone, hydrocodone, methadone, and fentanyl
`are on the rise, with a 149% increase in ED visits related
`to narcotic pain medications11,12 (Figure 1). A 2013
`review of opioid related deaths in Ontario, Canada
`demonstrated that heroin was associated with less
`than 2% of all deaths, while the most common opioids
`implicated were oxycodone, morphine, methadone,
`
`Downloaded by [NIH Library] at 14:40 15 March 2016
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`FIGURE1. Pattern of prescription opioid abuse 20042008.
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`552
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`PREHOSPITALEMERGENCYCARE OCTOBER/DECEMBER2014 VOLUME 18 / NUMBER4
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`codeine, and fentanyl.13 It is unclear whether current
`dosing regimens of IN naloxone are as effective in
`treating longer-acting, higher-potency opioids.
`These medications have different pharmacokinetics
`and pharmacodynamics than heroin. The fact that the
`opioid in this case was fentanyl, abused as a transder-
`mal patch, probably contributed to toxicity. Fentanyl
`is an opioid derivative 600 times as lipid soluble and
`100 times as potent as morphine. Fentanyl patches are
`notable for a prolonged duration of effect, even when
`used appropriately. Following removal of dermal
`patches, continued effects of respiratory depression
`and miosis may be seen for up to 24 hours.14 Route
`of exposure may also effect toxicity, and ingestion
`of fentanyl patches is an independent risk factor for
`overdose. Notable cases of fentanyl patch toxicity have
`required intubation, high-dose naloxone infusion, and
`resulted in death.15 A retrospective multisite case re-
`view determined that the most common related signs
`were coma,
`lethargy, and respiratory depression.16
`The majority required naloxone treatment. Of note,
`5.3% of these cases signed out against medical advice.
`Altered pharmacodynamics and pharmacokinetics
`may contribute to the staggering mortality associated
`with methadone, which represents 3% of opiate
`prescriptions but is responsible for almost a third
`of opioid-related deaths.17 This is highlighted in the
`graph below, illustrating that the duration of effects
`of opioid medications can range from hours to days,
`while the duration of effect of heroin rarely exceeds 30
`minutes18 (Figure 2).
`Another issue with intranasal administration of
`naloxone relates to poor bioavailability and unpre-
`dictable absorption and clinical effects.
`Intranasal
`naloxone has a 4% bioavailability, significantly reduc-
`ing serum levels. Typical intranasal administration
`protocols call for a one-size-fits-all (1 mg per nostril)
`
`dosing. When medical providers administer IV nalox-
`one, dosing may be adjusted to provide just enough
`antagonism to reverse apnea without precipitating
`withdrawal. Focus groups with IVDU report that they
`have a fear of precipitating dope sickness
`following
`administration of home naloxone.19 These users report
`that they would likely redose themselves with opioid
`medications to treat such withdrawal symptoms. Such
`behavior can be lethal. Death from overdose increases
`dramatically following recovery from nonfatal over-
`dose; opioid withdrawal triggered by intranasal nalox-
`one may be a powerful motivator to reuse and cause
`more harm than good.20
`The use of home naloxone to avoid involving
`medical professionals is a recurring theme, with THN
`participants exclaiming No one called 9-1-1 for the
`guy who was overdosing. They called me instead. 21
`Recipients of bystander initiated naloxone call 9-1-1
`about 31% of the time.22 Though often instructed to do
`so, this may not occur due to fear of legal repercussions
`or a misperception that once the person has woken
`up, they are safe.21 Many observers may ask if such
`avoidance is a problem if the patient has safely recov-
`ered from their overdose with a single dose of home
`naloxone. Unfortunately, current recommendations for
`staying with the patient until they have woken up
`underestimate the long duration of effect of commonly
`abused opiates, the short duration of effect of nalox-
`one, and the risk of recurrence of apnea. An opioid-
`na¨ve patient suffering the effects of a long acting opi-
`oid, such as methadone, may be at risk for respiratory
`depression several hours after the initial administra-
`tion of naloxone. When the primary use of naloxone
`was in heroin overdose, it may have been reasonable
`to set a 1-hour observation period; however, the
`changing face of an opioid overdose epidemic fueled
`by longer-acting opioids (with duration of effects from
`
`Downloaded by [NIH Library] at 14:40 15 March 2016
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`FIGURE2. Duration of effect of opioid medications in therapeutic use vs. overdose.
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`M. Zuckermanet al. PITFALLSOF INTRANASALNALOXONE
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`4 hours to 4 days) has led to a revision of post naloxone
`observation periods to a minimum of 46 hours. 18
`Patients who are left unobserved following home
`naloxone administration may at be increased risk.
`Extrapolations may be made from prior studies that
`explored the sequelae of patients refusing hospital
`transport following out-of-hospital naloxone. Most of
`these studies have found no immediate deaths.23,24
`Unfortunately, the inherent limitations in these study
`designs (review of local medical examiner records)
`may miss nonlethal morbidity and readministration
`of out of hospital naloxone. More rigorous follow-up
`of such patients is therefore needed. Though Wampler
`et al.23 report no deaths within 48 hours of receiving
`naloxone in patients who refused hospital transport,
`there was almost a 2% 30-day mortality rate. This is a
`dramatically higher mortality rate than the general
`population, and an even higher mortality rate than
`injection drug users as a group. The etiology of these
`deaths is unfortunately not listed but major sources
`of mortality in injection drug users include overdose,
`trauma, self-harm, and medical complications (pneu-
`monia, hepatitis, renal failure, etc.).25 It is possible that
`subsequent evaluation by a medical provider may
`have provided an opportunity for medical screening
`and intervention to prevent these deaths. Like any
`medical emergency, overdose is an opportunity for
`medical providers to intervene with at-risk individuals
`who might otherwise not be susceptible to counseling
`and intervention.26 The use of home naloxone by
`nonmedical providers may inadvertently prevent this
`encounter, robbing patients of an opportunity for
`intervention.
`Even more concerning in this case is the ever-
`increasing use of
`intranasal naloxone by trained
`paramedic responders. The argument may be made
`that intranasal home naloxone provides a simple way
`for non-medical providers to provide a life-saving
`intervention. However, every EMT has training in
`achieving IV access, which allows for careful par-
`enteral administration and titration of naloxone.
`The uniform dosing common to intranasal naloxone
`administration as well as the resultant avoidance of
`intravenous access do not seem to help the patient.
`Analogously, oral administration of furosemide may
`be more convenient for EMS personnel, but medical
`professionals recognize the advantages of parenteral
`administration in terms of dosing and effectiveness.
`A similar view must be taken of EMS administration
`of naloxone. A robust review of the use of intranasal
`naloxone by Kerr et al. discusses some of the promise
`of intranasal naloxone, but stops short of recommend-
`ing its widespread acceptance by EMS providers in
`the prehospital setting.27 In one retrospective review
`of a California EMS registry, 18% of IN naloxone re-
`cipients required additional doses and 6% required IV
`naloxone while failing to affect the rate of needle stick
`
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`
`exposures.7 Further research via EMS registries may
`provide reliable insight into the strengths and limita-
`tions of IN naloxone, especially given the variety of
`opioids that continue to appear. As recently as March
`2013, the unprecedented appearance of acetylfentanyl
`in Rhode Island and Pennsylvania resulted in opioid
`overdoses that required higher doses of naloxone.28
`CONCLUSION
`In conclusion, this case is presented as an example
`where administration of intranasal naloxone failed
`to resolve apnea and respiratory distress in the set-
`ting of fentanyl patch exposure. The choice of using
`intranasal naloxone when intravenous naloxone is
`readily available to EMS providers may have delayed
`definitive therapy. Additionally, enthusiasm for home
`naloxone programs as a panacea for treatment of the
`opioid overdose epidemic must be tempered with a
`better understanding of what we are treating. Early
`research into the success of bystander home-naloxone
`programs is promising, yet these programs focused
`largely on patients who had overdosed on short-acting
`heroin. The authors encourage, therefore, providers
`to be aware of the drawbacks in using intranasal
`naloxone in the setting of nonheroin opioid overdose
`and to continue to attempt titrated administration of
`parenteral naloxone by a medical provider. This is
`particularly important as deaths from drug overdose
`continue to mount, while heroin overdose becomes
`relatively less commonplace. Bottom line: Not every
`opioid overdose is the same.
`
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