HHS Public Access
`Author manuscript
`Prehosp Emerg Care. Author manuscript; available in PMC 2016 May 11.
`
`Published in final edited form as:
`Prehosp Emerg Care. 2014 ; 18(4): 550–554. doi:10.3109/10903127.2014.896961.
`
`Pitfalls of Intranasal Naloxone
`
`Matthew Zuckerman, MD, Stacy N. Weisberg, MPH, MD, FACEP, and Edward W. Boyer, MD,
`PhD, FACEP
`Department of Emergency Medicine, University of Massachusetts Medical School, Worcester,
`Massachusetts
`
`Abstract
`We present a case of failed prehospital treatment of fentanyl induced apnea with intranasal (IN)
`naloxone. While IN administration of naloxone is becoming more common in both lay and pre-
`hospital settings, older EMS protocols utilized intravenous (IV) administration. Longer-acting,
`higher potency 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
`understanding of the strengths and limitations of IN administration 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
`literature to opioids other than heroin and to IN routes of administration.
`
`Keywords
`prescription opioids; overdose; intranasal naloxone
`
`Introduction
`Every 14 minutes another young adult dies from drug overdose in the United States.1 Closer
`inspection reveals 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 overdose deaths. Though prescription of opioids
`varies 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, nonmedical 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 associated with nonmedical use of opioids. Initial studies focused on use of
`intramuscular naloxone to prevent death from heroin abuse.5,6 More recently intranasal
`
`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. Stacy.Weisberg@umassmemorial.org.
`The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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`Case
`
`naloxone has become available and more attractive to both prehospital providers and
`nonmedical personnel. 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 therapy for opioid
`overdose.7,8 While intranasal naloxone has allowed for needle-less bystander opioid
`overdose rescue, issues regarding bioavailability, titratability, effectiveness in cases of
`nonheroin overdose, and ultimately whether this delivery method is appropriate for first-line
`EMS response remain unclear. As with any therapeutic intervention, previously published
`case reports 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 improved ventilation, requiring the administration of
`intravenous (IV) naloxone.
`
`The patient was a 26-year-old male with history of opioid abuse who was found with agonal
`respirations, decreased mental status, and miotic pupils after intentionally masticating two
`25-µg fentanyl 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 intranasal naloxone for rescue in an
`undifferentiated opioid overdose. Naloxone has previously been administered 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 associated 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 administrations and adverse outcomes. At the same time, utilization of IN
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`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 indicate whether IN naloxone was successful. Before implementing 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
`studies focusing on bystander intervention are generalizable 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, 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 transdermal 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 review 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
`unpredictable absorption and clinical effects. Intranasal naloxone has a 4% bioavailability,
`significantly reducing serum levels. Typical intranasal administration protocols call for a
`one-size-fits-all (1 mg per nostril) dosing. When medical providers administer IV naloxone,
`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 overdose; opioid withdrawal triggered by
`intranasal naloxone may be a powerful motivator to reuse and cause more harm than good.20
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`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 “recovered” 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 naloxone,
`and the risk of recurrence of apnea. An opioid-naïve patient suffering the effects of a long
`acting opioid, such as methadone, may be at risk for respiratory depression several hours
`after the initial administration 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 4 hours to 4 days) has led to a revision of post naloxone observation periods
`to a minimum of 4–6 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 (pneumonia, 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
`parenteral 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
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`Kerr et al. discusses some of the promise of intranasal naloxone, but stops short of
`recommending its widespread acceptance by EMS providers in the prehospital setting.27 In
`one retrospective review of a California EMS registry, 18% of IN naloxone recipients
`required additional doses and 6% required IV naloxone while failing to affect the rate of
`needle stick exposures.7 Further research via EMS registries may provide reliable insight
`into the strengths and limitations 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 setting 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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`Figure 1.
`Pattern of prescription opioid abuse 2004–2008.
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`Figure 2.
`Duration of effect of opioid medications in therapeutic use vs. overdose.
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