Article, Emergency Medicine

Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication

a b s t r a c t

Objective: To describe the use and efficacy of nebulized naloxone in patients with suspected opioid intoxication.

Methods: This was an observational study conducted at an Inner city emergency department. Patients were eligible if they had self-reported or suspected opioid intoxication and a spontaneous respiratory rate

>=6 breaths/minute. Nebulized naloxone (2 mg in 3 mL normal saline) was administered through a standard face mask at the discretion of the treating physician. Structured data collection included demographics, vital signs pre and post Naloxone administration and adverse events. The primary outcome was level of consciousness, which was recorded pre and 15 minutes postnaloxone administration using the Glasgow Coma Scale (GCS) and the Richmond Agitation Sedation Scale (RASS).

Results: Of the 73 patients who presented with suspected opioid intoxication and were given naloxone over the study period, 26 were initially treated with nebulized naloxone. After nebulized naloxone administration, median GCS improved from 11 [interquartile range (IQR) 3.5] to 13 (IQR, 2.5), P = .001. Median RASS improved from -3.0 (IQR, -1.0) to -2.0 (IQR, -1.5), P b .0001. Need for supplemental oxygen decreased from 81% to 50%, P = .03. Vital signs did not differ pre/post therapy. There were few adverse effects from nebulized naloxone administration: 12% experienced moderate-severe agitation, 8% were diaphoretic and none vomited. Eleven required subsequent administrations of naloxone, nine of whom self-reported using either heroin, methadone or both. Of these, 5 underwent urine drug screening and all 5 tested positive for either opiates or methadone.

Conclusions: Nebulized naloxone was well-tolerated and led to a reduction in the need for supplemental oxygen as well as improved median GCS and RASS scores in patients with suspected opioid intoxication.

(C) 2013

Introduction

Over the past 2 decades, narcotic abuse in North America has escalated, creating an enormous burden on healthcare systems. Annual heroin-related emergency department (ED) visits in the United States have more than doubled, from 74,000 to 186,000 ED

? There was no funding for this investigation.

?? This study was, in part, presented at the Society for Academic Emergency

Medicine annual meeting in May, 2009. Haroz R, Patterson RA, Parone DA, Jones MK, Glaspey LJ, Smith NM, Stauss MP, Baumann BM. The efficacy of nebulized naloxone in comparison to intravenous and intranasal formulations. AcadEmerg Med. 2009;16(4):S220.

? This investigation was conducted at Cooper University Hospital, Camden, NJ.

* Corresponding author. Department of Emergency Medicine, Cooper University Hospital, One Cooper Plaza, Camden, NJ 08103, USA. Tel.: +1 856 342 2627; fax: +1

856 968 8426.

E-mail address: [email protected] (B.M. Baumann).

visits and non-medical abuse of Prescription opioids has increased by 50% in the United States and 25%in Canada [1,2]. Many of these patients undergo resuscitation in the field by emergency medical services providers and, to minimize prehospital provider exposure to blood-borne pathogens, the use of needleless naloxone has been advocated [3-8]. Most prehospital experience is with intranasal naloxone, where prefilled ampules containing 1 mg of naloxone each are administered via each nostril, yielding response rates ranging from 74-83% [3,5,7]. In spite of these promising findings, there are disadvantages to intranasal naloxone administration. Titration is difficult and patients may either experience Acute withdrawal symptoms or they may not have adequate opioid reversal [9,10]. Other means of needleless naloxone administration include oral and sublingual, but these have poor bioavailability [11,12].The endotra- cheal route may also be utilized, but this requires an intubated patient, and intubation is often the procedure that healthcare providers are trying to circumvent. Other than the intranasal route, the only other

0735-6757/$ – see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2012.10.004

586 B.M. Baumann et al. / American Journal of Emergency Medicine 31 (2013) 585588

means of needleless naloxone administration is via nebulization, however, this too is problematic. The extant supportive literature is limited to a case report and a retrospective series of patients in the prehospital setting [13,14]. Contradicting these is a small randomized controlled trial which demonstrated no difference between nebulized naloxone and placebo in reversing morphine-induced sedation in healthy, non-narcotic abusing volunteers [15]. Given these conflicting results and our dissatisfaction with intranasal naloxone, several of our physicians began using nebulized naloxone to reverse opioid intoxication. Our anecdotal experience was quite positive and in this investigation, we present our experiences with the use of nebulized naloxonein a convenience sample of patients with suspected opioid intoxication. Our primary objective in this pilot study was to describe improvements in Glasgow Coma Scale scores and Richmond Agitation Sedation Scale (RASS) scores post nebulized naloxone administration.

Materials and methods

Data were collected on adult patients presenting to the ED who were administered nebulized naloxone in order to reverse suspected opioid intoxication. To receive nebulized naloxone, patients required a minimum respiratory rate of 6 breaths per minute to ensure adequate delivery of the reversal agent. A depressed sensorium was not an exclusion to the administration of nebulized naloxone. Rather, a moderately depressed sensorium and a worsening or anticipated worsening respiratory status was often the reason it was utilized.

Systematic collection of data was allowed to proceed after review by our institutional review board (IRB) with the stipulation that any interventions were based solely upon physician preference, not a research protocol. Our original proposal to conduct a randomized controlled trial, comparing nebulized naloxone to intravenous administration was denied by our IRB due to the inclusion of vulnerable patients who could not provide informed consent. Instead, we were allowed to prospectively collect data as part of a quality assurance project. A de-identified database was developed for the analysis, which was deemed exempt from formal review by our IRB. The study was conducted in an inner city academic ED with an annual census of approximately 54,000. Patients were eligible for inclusion if they were 18 years and older, had not received naloxone in the prehospital setting, and received naloxone in nebulized form in the ED for the purpose of reversing suspected opioid intoxication. Opioid intoxication was defined a priori as any patient who arrived in the ED with either a depressed sensorium or respiratory drive and a history of opioid use as provided by either the patient or Prehospital providers. These criteria reflect published clinical criteria [16]. Data were collected from July 2007 to January 2009. Trained research assistants screened and enrolled all incoming patients from 9 AM to

11 PM, 7 days a week.

Patients who received nebulized naloxone in the ED setting were enrolled and received2 mg of naloxone mixed with 3 mL of normal saline. This solution was placed in a nebulizer face mask and the side ports were partially occluded with tape to prevent excessive loss of medication (Fig. 1).

Research assistants blinded to the objective of this investigation

Fig. 1. Example of nebulized naloxone delivery system in a volunteer. Note that the side ports of the face mask are occluded with tape to prevent escape of the nebulized naloxone.

of “response” versus “no response” [17-20]. The RASS was additionally calculated as this scale is specifically designed to assess sedation, a factor which often led to the administration of naloxone. Like the GCS, the RASS has been used in varioUS settings, is a validated scale, demonstrates high interrater reliability and is easy to perform [21-24]. The RASS ranges from +4 to -5, with values above zero corresponding to agitation. Patients who score a zero are alert and calm The remaining negative scores correspond to increasing levels of sedation as noted in the Appendix.

Descriptive statistics were used to describe sample characteristics. Continuous, normally distributed variables are presented as means with SDs, and for non-parametric data, medians and interquartile ranges (IQR) are noted. Pre and post naloxone data points were compared using paired Student’s t test for continuous variables and Fisher’s exact test for proportions. Nonparametric paired data were compared using the Wilcoxon test. Assuming a 2-sided ? of .05 and 80% power, we determined that 20 subjects were needed to demonstrate an improvement in GCS score of 2. Data were analyzed using SPSS version 16.0 (SPSS, Inc, Chicago, IL).

Results

During the screening period, 73 patients required naloxone for the reversal of suspected opioid intoxication. Of these, 19 received naloxone in the field and were excluded. Of the remaining 54, 26 patients were treated with nebulized naloxone in the ED. There were 15 (58%) men, 6 (26%) blacks, 2(8%) Hispanics and the median age of patients was 31.2 (IQR, 15.5) years. Pre and post naloxone vital signs, oxygen requirements, GCS and RASS scores are provided in Table 1. There were few adverse effects from the initial nebulized naloxone administration. Three (12%) experienced moderate-severe agitation,

2 (8%) were diaphoretic and none vomited. Four patients were admitted to the hospital and none was intubated.

Table 1

Patient characteristics and alertness

completed a structured data form on all patients who fulfilled

inclusion criteria, recording patients’ initial and repeat vital signs, results of urine Drug testing (if obtained by the treating physician) and subsequent naloxone administration. Vital signs and alertness using the GCS and RASS were recorded immediately before each naloxone dose and 15 minutes after the completion of the nebulized naloxone. The GCS was used as it is a common scale utilized in EDs, has been validated and can easily be calculated. Furthermore, the GCS has been used in prior opioid overdose investigations and provides a greater level of discrimination than the more subjective assessments

Characteristic Pre naloxone Post naloxone P

Vital signs, mean (SD) Pulse beat/min

93

(21)

87

(19)

.13

Systolic blood pressure mm Hg

137

(26)

132

(27)

.17

Diastolic blood pressure, mm Hg

81

(22)

79

(19)

.50

Respiratory rate

13

(5)

16

(4)

.11

Pulse oximetry, median (IQR)

96

(4)

98

(5)

.35

Required supplemental oxygen, n %

21

81%

13

50%

.03

GCS, median (IQR)

11.0

(3.5)

13.0

(2.5)

.001

Richmond Agitation Sedation Scale

-3.0

(-1.0)

-2.0

(-1.5)

b.0001

B.M. Baumann et al. / American Journal of Emergency Medicine 31 (2013) 585588 587

1Median time to second 2Times from second to naloxone administration: third naloxone administration: 33 (IQR, 62) minutes 30 minutes (nebulized IV) (range, 15-300 minutes) 63 minutes (nebulized IN)

Intranasal Naloxone (n = 1)

IV Naloxone (n = 1)

Nebulized naloxone (n = 8)1

Intranasal Naloxone (n = 1)2

Nebulized Naloxone (n = 26)

IV Naloxone (n = 1)

IV Naloxone (n = 2)

224 minutes (IV IV)

Fig. 2. Flow diagram of patients who received nebulized naloxone on arrival to the ED.

Confirmatory urine drug testing was at the discretion of the treating physician and was undertaken in 10 (39%) patients. Nineteen (73%) admitted to prior Heroin use, 10 (39%) admitted to methadone use and seven (27%) admitted using both. Every patient who admitted to some form of opioid use tested positive for opioids, methadone or both on urine drug screen. Of those who denied opioid use and underwent testing, 2 tested positive for opiates only. Polydrug use was common, with 2 patients testing positive for alcohol, 4 for benzodiazepines, 4 for tetrahydrocannabinol, and 7 for cocaine.

Repeat naloxone administration was required in eleven patients and a third dose was given to three patients. The route of administration was again at the discretion of the treating physician, with the majority receiving a repeat administration of nebulized naloxone (Fig. 2). Median time to second naloxone administration was 33 (IQR, 62) minutes (range, 15-300 minutes). Six patients received a second dose of naloxone within 33 minutes and the remaining 5 were given a second naloxone dose between 51 and 300 minutes. Self-report of illicit substance abuse and the results of the UDS testing in this subgroup are presented in Table 2.

Discussion

Conducting research using a Vulnerable patient population that is unable and often unwilling to provide informed consent for an agent

Table 2

Patient characteristics who required naloxone readministration

Time to Route of Self report Urine drug screen results readministration second dose

that reverses opioid intoxication is extremely challenging and likely explains the dearth of literature on the subject. Mycyk et al published the first successful use of serial administrations of nebulized naloxone in a 46-year-old former intravenous drug user who presented with lethargy and respiratory depression after ingesting methadone [13]. Nebulized naloxone was initially used to manage the patient because severe venous scarring delayed intravenous access. Two administra- tions were given, the first being so successful, it obviated the need for intubation. Upon admission to the intensive care unit, however, she was started on a naloxone infusion at 2 mg/hour which resulted in severe Opioid withdrawal, pulmonary edema, and consequent intubation. Mycyk and colleagues concluded that nebulized naloxone “gently and effectively” reverses opioid intoxication and called for additional studies to determine the minimal respiratory rate for nebulized naloxone to be effective, the optimal dose and whether their findings could be replicated by others [13]. Since then, only two other studies have been completed. Karras and colleagues random- ized healthy adult volunteers to one of three interventions: (1) 4 mg of nebulized naloxone and intravenous saline, (2) nebulized saline and 2 mg intravenous naloxone, or (3) nebulized and intravenous saline. The intravenous naloxone group fully reversed more quickly (3.0 minutes) than the nebulizer (14.5 minutes) or control (14.8 minutes) groups and the intravenous group had higher mental status scores than the nebulizer or control group between 2 and 8 minutes post treatment. Nebulizer and control groups did not differ in time to partial recovery, time to Full recovery, or in mental status at any time point. The authors admitted that their sample size was small, but concluded that nebulized naloxone did not appear to be effective in reversing opioid sedation [15]. A major limitation of the Karras study is that healthy volunteers were enrolled and morphine, not heroin or methadone, was the opiate used to induce sedation. In contrast, Weber and colleagues performed a retrospective analysis of 105 prehospital patients who received nebulized naloxone by the Chicago Fire Department, where 22% of patients had complete response and 59% had partial response. Limitations to this investigation include a lack of GCS scoring prior to administration of naloxone and no report of urine drug testing data [14].

Our findings were much more positive and paralleled those of Mycyk and Weber and colleagues. We demonstrated that nebulized naloxone decreases the need for supplemental oxygen and improves GCS and RASS scores with minimal adverse effects. Nearly 60% required no additional interventions, and of those who did require subsequent naloxone administrations, polypharmacy was common (early readministration) as was self-reported methadone use (late readministration). In patients who have used multiple illicit sub- stances, the effects of the nebulized naloxone may be blunted or prematurely obscured by the other substances. In patients who consumed methadone, the prolonged half-life of the methadone would require subsequent doses of naloxone to maintain a patient’s respiratory drive.

An additional benefit of naloxone, which was not utilized in this

15 min Nebulized Heroin, methadone

Benzo, cocaine, opiates, methadone

investigation, is its titratability. Unlike the intranasal formulation, which is administered as a rapid nasal bolus, nebulized naloxone can

25 min Nebulized Heroin Cocaine, opiates
  • 25 min Intranasal Heroin, methadone
  • Benzo, cocaine, THC, opiates, methadone

    be removed once the patient is sufficiently alert. The goal in naloxone administration is a patient who is no longer hypoxic and one who can

    27 min Nebulized Cocaine Cocaine, THC, opiates
  • 30 min Nebulized Heroin No UDS
  • 33 min Nebulized Denied drug use No UDS
  • 51 min Intravenous Heroin No UDS
  • protect his airway. Rendering someone fully alert is often counter- productive since it is frequently accompanied by severe agitation and Withdrawal symptoms, and, may lead to elopement attempts [13].

    61 min Nebulized Heroin, methadone
  • 90 min Intravenous Heroin, methadone,
  • cocaine

    No UDS

    THC, opiates, methadone

    There are several limitations of this investigation. This was a convenience sample which captured patients presenting between 9 AM to 11 PM, so our sample may be subject to selection bias. However, our site is located in an inner city where illicit drug purchase and use is

    107 min Nebulized Methadone No UDS

    conducted by both city residents and suburban users. As we encounter

    300 min Nebulized Heroin, methadone

    No UDS

    opioid overdoses in both populations during daylight hours as well as during the night, we think that potential selection bias is minimal

    Benzo, benzodiazepines; THC, tetrahydrocannabinol; UDS, urine drug screen.

    [25]. We were unable to control for polypharmacy or other illicit drug

    588 B.M. Baumann et al. / American Journal of Emergency Medicine 31 (2013) 585588

    use and we also did not conduct confirmatory drug testing in all patients. Thus, it remains unknown what proportion of patients presented with heroin, methadone, prescription opioid or polysub- stance abuse. We were unable to enforce such testing, and, likewise, unable to utilize a more rigorous study design due to existing regulations on exception from informed consent for emergency research. Such an undertaking would have required significant financial support to enable community consultation and public disclosure to potentially eligible patients. Finally, we were unable to refine the indications for when nebulized naloxone may be admin- istered. Our physicians used a respiratory rate cutoff of <=6 breaths/ minute, but we did not determine the lower limits in respiratory rate, oxygen saturation, or alertness. This too was beyond the scope of this investigation. In spite of these limitations, our study remains the only prospective investigation of the use of nebulized naloxone in suspected opioid Intoxicated patients.

    Conclusion

    We demonstrated that nebulized naloxone reduces the need for supplemental oxygen and results in improvements in GSC and RASS scores. We anticipate that our findings will encourage the completion of more controlled investigations. Further study is needed to better identify the patient population in which nebulized administration is most efficacious as well as a comparison in alertness scores between nebulized and other routes of naloxone administration.

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      Appendix. Richmond Agitation Sedation Scale?

      alternative for treatment of opioid overdose in the prehospital setting. J Emerg

      Med 2005;29(3):265-71.

      Kelly AM, Koutsogiannis Z. Intranasal naloxone for life threatening opioid toxicity. Emerg Med J 2002;19:375.

    19. Kelly AM, Kerr D, Dietze P, et al. Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust 2005;182(1):24-7.
    20. occupational exposure to bloodborne pathogens–OSHA. Final Rule. Fed Regist 2001;66:5317-25. http://www.osha.gov/pls/oshaweb/owadisp.show_document?

      Score Term Description

      0 Alert and calm

      -1 Drowsy Not fully alert, but has sustained

      awakening(eye-opening/eye contact) to

      voice (N 10 seconds)

      p_id=16265&p_table=FEDERAL_REGISTER (Accessed November 5, 2012).

      Kerr D, Kelly AM, Dietze P, et al. Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction 2009;104(12):2067-74.

    21. Robertson TM, Hendey GW, Stroh G, et al. Intranasal versus intravenous naloxone for prehospital narcotic overdose. Acad Emerg Med 2005;12((5) suppl 1):166-7.
    22. Dowling J, Isbister GK, Kirkpatrick CM, et al. Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther

      -2 Light sedation

      -3 moderate sedation

      -4 deep sedation

      Briefly awakens with eye contact to voice

      (b 10 seconds)

      Movement or eye opening to voice (but no eye contact)

      No response to voice, but movement or eye opening to physical stimulation

      Drug Monit 2008;30(4):490-6.

      Loimer N, Hofmann P, Chaudhry HR. Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict 1994;29(6): 819-27.

      -5 Unarousable No response to voice or physical stimulation

      * This Appendix only provides the sedation portion of the Richmond Agitation Sedation Scale.

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