INTRANASAL NALOXONE IS A VIABLE ALTERNATIVE TO INTRAVENOUS
`NALOXONE FOR PREHOSPITAL NARCOTIC OVERDOSE
`Tania Mieke Robertson, MD, Gregory W. Hendey, MD, Geoff Stroh, MD,
`Marc Shalit, MD
`
`ABSTRACT
`
`Objective. To compare the prehospital time intervals from
`patient contact and medication administration to clinical re-
`sponse for intranasal (IN) versus intravenous (IV) nalox-
`one in patients with suspected narcotic overdose. Meth-
`ods. This was a retrospective review of emergency medical
`services (EMS) and hospital records, before and after im-
`plementation of a protocol for administration of intranasal
`naloxone by the Central California EMS Agency. We in-
`cluded 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 elec-
`tronic 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 pa-
`tient contact to clinical response. Secondary variables in-
`cluded 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 ap-
`propriate. 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, respec-
`tively (p = 0.3). The mean time between naloxone admin-
`istration 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 signif-
`icantly 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 ad-
`ministration to clinical response for naloxone was longer
`for the IN route, but the overall time from patient con-
`tact 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 nalox-
`one appears to be a useful and potentially safer alternative.
`
`Received January 19, 2009, from the Department of Emergency
`Medicine, UCSF–Fresno, Medical Education Program (TMR, GWH,
`GS, MS), Fresno, California. Revision received March 2, 2009; ac-
`cepted for publication March 17, 2009.
`The authors have no conflicts of interest for this study.
`Address correspondence and reprint requests to: Gregory Hendey,
`MD, UCSF Fresno Medical Education & Research Center, Depart-
`ment of Emergency Medicine, 155 North Fresno Street, Suite 206,
`Fresno, CA 93701. e-mail: ghendey@fresno.ucsf.edu
`doi: 10.1080/10903120903144866
`
`Key words: naloxone; narcotic overdose; emergency medical
`services; intranasal
`PREHOSPITAL EMERGENCY CARE 2009;13:512–515
`
`INTRODUCTION
`Naloxone (Narcan) is a competitive antagonist of the
`mu-opioid receptor.1 It has long been used in the emer-
`gency setting to reverse the effects of opioid toxicity,
`and can be lifesaving for patients who have significant
`respiratory and mental status depression. There are a
`number of possible modes of administration for nalox-
`one, including intravenous (IV), intramuscular (IM),
`subcutaneous (SQ), endotracheal, sublingual, inhaled,
`and intranasal (IN).2,3 The IV route is the most com-
`monly used because it is both rapid and predictable in
`its clinical effects.
`To date, there have been only a handful of studies
`comparing the different modes of naloxone adminis-
`tration. Wanger et al. compared the prehospital use of
`naloxone by the IV and SQ routes.4 They found that al-
`though the IV route had a more rapid effect once given,
`SQ naloxone was administered more quickly, and the
`overall time from patient contact to clinical effect was
`nearly the same. A prospective study of 30 patients in
`Denver evaluated IN naloxone as the first-line agent in
`the prehospital setting in narcotic overdose.5 Of the 11
`patients who responded to either IN or IV naloxone,
`91% responded to IN naloxone alone. Of those treated
`with IN naloxone, 64% did not require IV access in the
`field. Kelly and Koutsogiannis compared IN naloxone
`with IM naloxone in Australia. In a preliminary report,
`they noted a 100% response rate with IN naloxone for
`six trial patients.6 In a subsequent prospective random-
`ized trial, Kelly et al. found the IM route to be faster
`than IN administration (6 vs. 8 minutes).7 The success
`rate for the patients treated with IN naloxone was 74%,
`and there was no difference between the groups in res-
`cue doses needed.
`Additionally, IN administration of naloxone may re-
`duce the risk of needlestick in a clinical setting where
`hepatitis, human immunodeficiency virus (HIV), and
`difficult IV access are common. Patients with altered
`mental status or narcotic overdose may require IV ac-
`cess for other reasons. However, as noted by Barton et
`al., those with isolated narcotic overdose who rapidly
`respond to IN naloxone may not require IV access at
`all.5
`
`512
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`Robertson et al.
`
`INTRANASAL NALOXONE FOR OPIOID OVERDOSE
`
`513
`
`The main objective of our study was to compare the
`IV and IN routes of naloxone administration with re-
`spect to the time from patient contact and medication
`administration to clinical effect in patients with sus-
`pected narcotic overdose. We also sought to assess the
`positive clinical response rate, need for repeat or rescue
`doses, and whether any needlesticks occurred during
`the care of the study patients.
`
`METHODS
`We performed a retrospective review of electronic
`emergency medical services (EMS) records. In March
`2004, the local EMS protocol was changed, making IN
`naloxone the first-line route of administration in pa-
`tients with suspected narcotic overdose. (See Table 1
`for the protocol.) The study period included March
`2003 through July 2004. Thus, in the first year of the
`study period, IV naloxone was the first-line agent, and
`in the final five months, IN naloxone was the first-line
`agent. The patient population selected for this study
`included those patients transported by EMS during the
`study period who were treated with naloxone for sus-
`pected narcotic overdose. In our system, patients must
`be clinically suspected of opiate intoxication and have
`a respiratory rate (RR) of 8 breaths/min or less to re-
`ceive naloxone. Exclusion criteria consisted of failure
`to be treated with naloxone and altered mental status
`that was not thought to be secondary to narcotic over-
`dose.
`The prehospital record is entirely electronic, with all
`patient care data uploaded into a single EMS database.
`We extracted the data relevant to our study, including
`all prehospital times, vital signs, patient assessments,
`and medications administered. We imported the ex-
`tracted data into a Microsoft Excel 2000 spreadsheet
`(Microsoft Corp., Redmond, WA) and stripped it of
`unique patient identifiers.
`Main outcome measures included time from nalox-
`one administration to clinical response and time from
`
`TABLE 1. Intranasal Naloxone Protocol from the Central
`California EMS Agency
`
`Naloxone
`Intranasal (IN)—Administer 2 mg intranasally (1 mg per nostril)
`using a mucosal atomizer device (MAD) if suspected narcotic
`intoxication and respiratory depression (rate 8 breaths/min or
`less) are present. This dose may be repeated in 5 minutes if
`respiratory depression persists. Respirations should be supported
`with BVM until the respiratory rate is >8 breaths/min.
`Intramuscular (IM)—Administer 1 mg if unable to administer
`intranasally. May repeat once in 5 minutes.
`Intravenous (IV)—Administer 1 mg via slow IV push if there is no
`response to intranasal or intramuscular administration after
`10 minutes.
`Pediatric dose—Administer 0.1 mg/kg intranasally, if the patient
`weighs less than 10 kg and is less than 1 year old.
`BVM = bag–valve–mask; EMS = emergency medical services.
`
`TABLE 2. Characteristics of the Study Group
`
`IV
`IN
`Naloxone Naloxone
`
`p-Value
`
`All patients (N)
`Age—mean (range), years
`Gender—male (%)
`Initial GCS score—mean
`Initial RR—mean, breaths/min
`Initial SBP <100 mmHg (%)
`
`50
`41 (18–72)
`71%
`6.2
`8.6
`10%
`
`104
`44 (3–96)
`60%
`6.9
`10.9
`20%
`
`0.21
`0.14
`0.28
`0.06
`0.11
`
`58
`33
`Responders only (n)
`0.36
`5.8
`5.2
`Initial GCS score—mean
`0.08
`9.1
`7.0
`Initial RR—mean, breaths/min
`GCS = Glasgow Coma Scale; IN = intranasal; IV = intravenous; RR = respi-
`ratory rate; SBP = systolic blood pressure.
`
`patient contact to clinical response. Secondary out-
`come measures included numbers of doses adminis-
`tered, rescue doses given by an alternate route, and
`needlesticks reported during the care of study patients.
`We defined a positive clinical response as an increase
`in RR of at least 6 breaths/min or improvement in
`the Glasgow Coma Scale (GCS) score of at least 6
`points.
`Between-group comparisons were accomplished us-
`ing t-tests and chi-square tests as appropriate. The
`study was approved by the hospital institutional re-
`view board and the Central California EMS Medical
`Control Committee.
`
`RESULTS
`There were 154 patients during the study period who
`met inclusion criteria. Characteristics of the study
`group are reported in Table 2. Per protocol, 104 re-
`ceived IV naloxone as first-line therapy, and 50 re-
`ceived IN naloxone. Positive clinical response, as pre-
`viously defined, was seen in 33 of 50 (66%) patients in
`the IN group and in 58 of 104 (56% patients in the IV
`group (p = 0.3). Changes in GCS score and RR in pa-
`tients with a positive clinical response to naloxone are
`reported in Table 3.
`Time intervals are reported in Fig. 1. It took longer
`for
`the IN naloxone to take effect (12.9 vs. 8.1 min,
`p = 0.02), but the total time from patient contact to
`
`TABLE 3. Changes in Mean Glasgow Coma Scale Score and
`Respiratory Rate after Treatment of Positive Responders to
`Naloxone
`
`Pretreatment
`
`Posttreatment
`
`p-Value
`
`Intranasal (n = 33)
`GCS score
`RR, breaths/min
`Intravenous (n = 58)
`5.8
`GCS score
`9.1
`RR, breaths/min
`GCS = Glasgow Coma Scale; RR = respiratory rate.
`
`5.2
`7.0
`
`13.1
`16.9
`
`12.7
`17.8
`
`0.0001
`0.0001
`
`0.0001
`0.0001
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`IN
`IV
`
`p=0.9
`
`20.3
`
`20.7
`
`p=0.02
`
`12.9
`
`8.1
`
`514
`
`30
`
`25
`
`20
`
`15
`
`10
`
`05
`
`Minutes
`
`Drug to Clinical Response
`Patient Contact to Clinical
`Time
`Response Time
`FIGURE 1. Time intervals in minutes. IN = intranasal; IV = intra-
`venous.
`
`clinical response was the same for the two groups
`(20.3 vs. 20.7 min, p = 0.9). We performed a post-hoc
`power calculation based on our data and found that
`we had a power of 83% to detect a difference of 20%
`(4 minutes) in the time from patient contact to clinical
`response.
`In the IN group, 34% (17/50) of patients were given
`a second dose of naloxone, while in the IV group, 18%
`(19/104) required a second dose (p = 0.05). In addi-
`tion, three patients in the IN group received a rescue
`dose of naloxone by an alternate route, while no pa-
`tients (6% vs. 0%, p = 0.19) in the IV group received
`a rescue dose by another route (Fig. 2). No needle-
`stick injuries were reported by EMS providers in either
`group.
`
`DISCUSSION
`We found that the administration of naloxone by the
`IN route is a useful alternative to the IV route in the
`prehospital setting. Prior to the initiation of the pro-
`
`%
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`p=0.3
`
`66
`
`56
`
`IN
`IV
`
`p=0.05
`
`34
`
`18
`
`p=0.19
`
`6
`
`0
`
`Clinical
`Response
`
`2 Doses of
`Subsequent
`Naloxone
`IV/IM Naloxone
`Needed
`Needed
`FIGURE 2. Clinical response rates (%) and rescue doses needed. IM =
`intramuscular; IN = intranasal; IV = intravenous.
`
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`PREHOSPITAL EMERGENCY CARE OCTOBER/DECEMBER 2009 VOLUME 13 / NUMBER 4
`
`tocol change, there were some concerns by the med-
`ical control committee and the medics themselves re-
`garding the efficacy of IN naloxone. However, IN ad-
`ministration of naloxone is now well received by our
`prehospital community. In addition, the EMS system
`has implemented protocols that utilize IN midazolam
`and glucagon.
`There are a number of potential advantages to the
`IN administration of naloxone in the prehospital set-
`ting, in the emergency department, in the clinic, and
`even in layperson applications. IN naloxone offers a
`needleless alternative that may be lifesaving or spare
`a patient intubation if IV access cannot be quickly
`established. Other potential applications include clin-
`ics for drug users, rehabilitation programs, patients at
`home on high-dose opioids, methadone clinics, drug
`resource centers, or needle exchange programs. Such
`uses would require careful study, because it may cre-
`ate other problems, such as emboldening users to be
`more cavalier with narcotic dosing. IN naloxone could
`potentially be used by laypersons in emergency situa-
`tions when access to health care is limited or unavail-
`able. This has already been done with IN glucagon in
`diabetic patients.8 However, one potential concern is
`that a false sense of security that lay rescue naloxone
`will cure “any case” of altered mental status could lead
`to harmful delays in EMS activation when the change
`in mental status is not secondary to narcotic intoxica-
`tion.
`With respect to prehospital personnel safety, body
`fluid exposures are a significant concern. A study
`done by the St. Louis EMS system reported 44 needle-
`stick injuries in a 38-month period.9 This equated to
`145 injuries per 1,000 employee-years. Two of those
`employees developed clinically apparent hepatitis B
`during the study period. After accidental percuta-
`neous exposure, the Centers for Disease Prevention
`and Control (CDC) reports a transmission rate of
`1.8% for hepatitis C, 6–30% for hepatitis B, and 0.3%
`for HIV.10 These statistics underscore the importance
`of implementing alternative methods of medication
`administration.
`
`LIMITATIONS AND FUTURE RESEARCH
`There were a number of limitations to our study. First,
`because of the retrospective design of the study, we en-
`countered missing data points for some patients. The
`time intervals we calculated were based on documen-
`tation by paramedics. The time intervals were longer
`than expected; however, the data-collection methods
`could have led to error in either direction. This ob-
`servation is likely due to the fact that ongoing pa-
`tient care is the top priority, and documentation fre-
`quently occurs after hospital arrival, with providers
`relying on memory and notes. The electronic record
`automatically records interactions with the dispatch
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`Robertson et al.
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`INTRANASAL NALOXONE FOR OPIOID OVERDOSE
`
`515
`
`center, such as the en route and hospital arrival times,
`but medication times and clinical responses are input
`individually. However, it seems unlikely that this type
`of error would bias the study results, as it presum-
`ably affected the IV and IN groups equally. Future
`studies in this area would be improved by accurate,
`real-time recording of treatment and clinical response
`times.
`Another potential limitation is the inadvertent in-
`clusion of cases that were not narcotic overdoses. We
`included all suspected cases of narcotic overdose in
`which paramedics treated the patient with naloxone,
`and we did not require confirmation of narcotics by
`toxicologic assays. However, the cases of misdiagno-
`sis were likely spread equally between the two groups,
`thus enabling comparison without significant bias.
`Furthermore, our selection methodology may have
`missed some cases of narcotic overdose or cases in
`which naloxone was not administered. Although our
`choice to include all patients with suspected narcotic
`overdose per the assessment of the paramedic on scene
`may have resulted in some inaccuracies, it bolsters the
`external validity by mirroring the actual practice of
`prehospital medicine.
`Our definition of a ”positive response” to naloxone
`was arbitrary. We chose to define it in such a way that
`would represent a large, clinically significant change
`that was relatively objective by chart review. Although
`our definitions might have caused us to misclassify
`some responses as positive or negative, it is unlikely
`that the bias would favor either the IV or IN group.
`Also, our sample size was too small for meaningful
`subgroup analysis or to detect any needlesticks. Fi-
`nally, we included only the more urban regions of our
`system, because these use an electronic record, which
`was used for data collection. Thus, patients in rural set-
`tings were disproportionately underrepresented. In-
`clusion of such patients might have altered the data in
`a number of ways, including more time to observe for
`clinical effects, establish IV access, or administer mul-
`tiple doses of medication.
`
`CONCLUSIONS
`We found that although IN naloxone had a slower on-
`set of action than the IV route, the overall time from pa-
`tient contact to clinical effect was the same. Intranasal
`naloxone represents a more gradual and potentially
`safer way to reverse the effects of opioid overdose.
`Intranasal naloxone is a useful alternative in patients
`with suspected narcotic overdose in the prehospital
`setting and it potentially offers a decreased risk to the
`EMS providers caring for patients with difficult IV ac-
`cess and a relatively high prevalence of blood-borne
`pathogens.
`
`References
`
`1. Reisine T, Pasternak G. Opioid analgesics and antagonists. In:
`Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman
`AG. Goodman and Gilman’s Pharmacologic Basis of Therapeu-
`tics, 9th edition. Toronto, Ontario, Canada: McGraw-Hill, 1996,
`pp 549–51.
`2. Marx JA, Hockberger RS, Walls RM. Rosen’s Emergency
`Medicine, 5th Edition. St. Louis, MO: Mosby, 2002, p 2184.
`3. Popa V, Rients B. The effect of inhaled naloxone on resting
`bronchial tone and exercise-induced asthma. Am Rev Respir Dis.
`1989;139:702–9.
`4. Wanger K, Brough L, Macmillan I, et al. Intravenous vs subcu-
`taneous naloxone for out-of-hospital management of presumed
`opioid overdose. Acad Emerg Med. 1998;5:293–9.
`5. Barton ED, Ramos J, Colwell C, et al. Intranasal administration
`of naloxone by paramedics. Prehosp Emerg Care. 2002;6:54–8.
`6. Kelly AM, Koutsogiannis Z. Intranasal naloxone for life threat-
`ening opioid toxicity. Emerg Med J. 2002;19:375.
`7. Kelley AM, Kerr D, Dietz P, et al. Randomized trial of intranasal
`versus intramuscular naloxone in prehospital treatment for sus-
`pected opioid overdose. MJA. 2005;182(1):24–7.
`8. Pontiroli AE, Calderara A, Pajetta E, et al. Intranasal glucagon
`for remedy of hypoglycemia. Studies in healthy subjects and
`type 1 diabetic patients. Diabetes Care. 1989;12:604–8.
`9. Hochreiter MC, Barton LL. Epidemiology of needlestick injury in
`emergency medical service personnel. J Emerg Med. 1988;6(1):9–
`12.
`10. National Center for Infectious Diseases, Centers for Disease Con-
`trol and Prevention. Exposure to blood: what healthcare person-
`nel need to know. July 2003. Available at: http://www.cdc.gov/
`ncidod/dhqp/pdf/bbp/Exp to Blood.pdf. Accessed July 28,
`2009.
`
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