Evidence-Based Guidelines for EMS Administration of Naloxone

Figures & data

Table 1. Members of Technical Expert Panel

Name	Area(s) of Expertise	Institution
James Gasper, PharmD, BCPP	Pharmacology	Pharmacy Benefits Division, California Department of Health Care Services
Jeffrey Goodloe, MD Co-Investigator (ACEP)	EMS Medical Direction Emergency Medicine	American College of Emergency Physicians (ACEP) Emergency Medical Services System for Metropolitan Oklahoma City & Tulsa Oklahoma Center for Prehospital & Disaster Medicine
Richard Hale	Performance Measure Development	ESO Solutions
Vicki L. Hildreth, BA, EMT-B	Patient Advocate EMS Clinician Pediatrics	WV Department of Health & Human Resources
Eddy Lang, MDCM, CCFP (EM)	EBG Development Emergency Medicine GRADE Methodology	Emergency Medicine Department, Cumming School of Medicine, University of Calgary, Alberta Health Services
John W. Lyng, MD, EMT-P Co-Investigator (NAEMSP)	EMS Medical Direction Emergency Medicine	North Memorial Health Ambulance & Air Care (Minneapolis, MN) National Association of EMS Physicians (NAEMSP)
Anne Montera, RN, BSN*	Patient Advocate	Caring Anne Consulting, LLC
Ashish R. Panchal, MD, PhD	Emergency Medicine EMS Medical Direction Research	National Registry of EMTs (NREMT) Department of Emergency Medicine, The Ohio State University Wexner Medical Center
Tim Seplaki, NRP*	EMS Clinician	NJ Department of Health, Office of EMS
Sharon Stancliff, MD	Addiction Medicine	Harm Reduction Coalition
Nate Sullivan, EMT-P*	EMS Clinician	Cherokee County Fire & Emergency Services
Peter Taillac, MD	EMS Medical Direction Prehospital Guidelines Consortium EBG Development Performance Measure Development	Bureau of EMS and Preparedness, Utah Department of Health
Debbie Vass, RN, EMT-P	EMS Administration Clinician Performance Measure Development	Sunstar Paramedics Paramedics Plus
Kenneth A Williams, MD Principal Investigator (NASEMSO)	EMS Medical Direction Emergency Medicine	Brown Department of Emergency Medicine Rhode Island Dept. of Health National Association of State EMS Officials (NASEMSO)

Staff and Federal Partner Support: Mary Hedges, Project Manager; Zoe Renfro, Project Coordinator; Dia Gainor, NASEMSO Executive Director; Dave Bryson, NHTSA Office of EMS; Jeremy Kinsman*, NHTSA Office of EMS; Cathy Gotschall, NHTSA Office of EMS

*New members added in April 2018. Most members were added in November 2017.

Table 2. PICO questions in the AHRQ Review (10)

Number	PICO Question
1	For patients with confirmed or suspected opioid overdose, what are the comparative benefits and harms related to out-of-hospital administration of naloxone by EMS personnel using intravenous, intramuscular, subcutaneous, and intranasal routes of administration?*
1a	For patients with confirmed or suspected opioid overdose who are administered naloxone in the out-of-hospital setting by EMS personnel, what are the comparative benefits and harms of different intravenous, intramuscular, subcutaneous, or intranasal doses of naloxone?^†
2	For patients with confirmed or suspected opioid overdose in out-of-hospital settings, what are the comparative benefits and harms of titration of naloxone administered by EMS personnel until the patient resumes sufficient spontaneous respiratory effort versus until the patient regains consciousness?
3	For patients with confirmed or suspected opioid overdose in out-of-hospital settings treated with multiple doses of naloxone (including patients who do not improve after an initial dose of intranasal naloxone), what are the effects on benefits and harms of differences in timing of repeat dosing?
4	For patients with confirmed or suspected opioid overdose in out-of-hospital settings who regain sufficient spontaneous respiratory effort and are alert and oriented after naloxone administration by EMS personnel, what are the benefits and harms of transporting patients to a health care facility vs. nontransport?

*To incorporate practitioner safety concerns, the TEP agreed to modify PICO Question 1 as it appeared in the AHRQ review. Question 1 from the AHRQ review is as follows:

For patients with confirmed or suspected opioid overdose, what are the comparative benefits and harms of out-of-hospital administration of naloxone by EMS personnel using intravenous, intramuscular, subcutaneous, and intranasal routes of administration?

^†To limit the scope of Question 1a to administration of naloxone by EMS practitioners, the TEP agreed to modify PICO Question 1a as it appeared in the AHRQ review. Question 1a from the AHRQ review is as follows:

For patients with confirmed or suspected opioid overdose who receive naloxone in the out-of-hospital setting from EMS personnel, what are the comparative benefits and harms of different intravenous, intramuscular, subcutaneous, or intranasal doses of naloxone?

Figure 1. Literature flow diagram from AHRQ systematic review entitled “Management of Suspected Opioid Overdose with Naloxone by Emergency Medical Services Personnel.” Figure reprinted with permission from the AHRQ.

Table 3. Articles identified by the AHRQ systematic review (10) in the four key areas

PICO Number and Area	Number of Articles Identified	Literature Identified
1. Route of Administration and 1a. Dose	7	Kelly AM, Kerr D, Dietze P, et al. Randomized trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust. 2005 Jan 3;182(1):24–7. PMID: 15651944. 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 Dec;104(12):2067–74. doi: 10.1111/j.13600443.2009.02724.x. PMID: 19922572. Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, et al. Naloxone therapy in opioid overdose patients: intranasal or intravenous? a randomized clinical trial. Arch Med Sci. 2014 May 12;10(2):309–14. doi: 10.5114/aoms.2014.42584. PMID: 24904666. Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses. Am J Emerg Med. 2010 Mar;28(3):296–303. doi: 10.1016/j.ajem.2008.12.009. PMID: 20223386. Robertson TM, Hendey GW, Stroh G, et al. Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp Emerg Care. 2009 Oct-Dec;13(4):512–5. doi: 10.1080/10903120903144866. PMID: 19731165. Sporer KA, Firestone J, Isaacs SM. Out-of hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med. 1996 Jul;3(7):660–7. PMID: 8816181. Wanger K, Brough L, Macmillan I, et al. Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med. 1998 Apr;5(4):293–9. PMID: 9562190.
2. Dose Titration of Naloxone	0
3. Repeat Dosing of Naloxone	0
4. Transport/ Non-Transport	6	Boyd JJ, Kuisma MJ, Alaspaa AO, et al. Recurrent opioid toxicity after pre-hospital care of presumed heroin overdose patients. Acta Anaesthesiol Scand. 2006 Nov;50(10):1266–70. PMID: 17067327. Levine M, Sanko S, Eckstein M. Assessing the risk of prehospital administration of naloxone with subsequent refusal of care. Prehosp Emerg Care. 2016;20(5):566–9. PMID: 27018626. Rudolph SS, Jehu G, Nielsen SL, et al. Prehospital treatment of opioid overdose in Copenhagen--is it safe to discharge on-scene? Resuscitation. 2011 Nov;82(11):1414–8. doi: 10.1016/j.resuscitation.2011.06.027. PMID: 21745532. Vilke GM, Buchanan J, Dunford JV, et al. Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehosp Emerg Care. 1999 JulSep;3(3):183–6. PMID: 10424852. Vilke GM, Sloane C, Smith AM, et al. Assessment for deaths in out-of-hospital heroin overdose patients treated with naloxone who refuse transport. Acad Emerg Med. 2003 Aug;10(8):893–6. PMID: 12896894. Wampler DA, Molina DK, McManus J, et al. No deaths associated with patient refusal of transport after naloxone-reversed opioid overdose. Prehosp Emerg Care. 2011 JulSep;15(3):320–4. doi: 10.3109/10903127.2011.569854. PMID: 21612385.

Table 4. GRADE Table for Recommendation 1: Intranasal (IN) vs. Intramuscular (IM)

Summary of findings:
Intranasal naloxone compared to intramuscular naloxone for suspected opioid poisoning
Patient or population: suspected opioid poisoning Setting: prehospital Intervention: intranasal naloxone Comparison: intramuscular naloxone
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with intramuscular naloxone	Risk with intranasal naloxone
GCS > 11 at 8 minutes (GCS > 11 at 8 minutes)	718 per 1,000	0 per 1,000 (0 to 0)	not estimable	155 (1 RCT)^†	⨁◯◯◯ VERY LOW^‡,§‖,#
Mean Response Time (min) (Mean Response Time)	The mean mean Response Time (min) was 0	The mean mean Response Time (min) in the intervention group was 0 (0 to 0)	–	14 (2 RCTs)**	⨁◯◯◯ VERY LOW^‡,§,‖,#
Proportion requiring rescue naloxone (Proportion requiring rescue naloxone)	not pooled	not pooled	not pooled	155 (2 RCTs)^†,**	⨁◯◯◯ VERY LOW^‡,§,‖,#
Adverse Response (Major; e.g. seizure) (Adverse Response (Major))	not pooled	not pooled	not pooled	155 (2 RCTs)**	⨁◯◯◯ VERY LOW^‡,§,‖,#
Adverse Response (Minor; e.g. agitation, irritation, nausea/vomiting, headache, tremor, sweating) (Adverse Response (Minor))	not pooled	not pooled	not pooled	155 (2 RCTs)**	⨁◯◯◯ VERY LOW^‡,§,‖,#
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

^†Kelly.

^‡Difference in baseline characteristics, Inadequate blinding of practitioners, post randomization exclusions.

^§One study showed no difference, another showed IN inferior to IM.

^‖The Australian IN formulation was different than that which is in current use. Current IN more effective with more potential for adverse events, not all EMS systems have made the switch however.

^#Small sample size and wide confidence intervals.

**Kelly and Kerr from Australia.

Table 5. GRADE Table for Recommendation 2 - Intranasal (IN) vs. Intravenous (IV)

Summary of findings:
Intranasal naloxone compared to intravenous naloxone for suspected opioid poisoning
Patient or population: suspected opioid poisoning Setting: prehospital Intervention: intranasal naloxone Comparison: intravenous naloxone
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with intravenous naloxone	Risk with intranasal naloxone
Respiratory Rate (5 minutes after administration)	The mean respiratory Rate (5 minutes after administration) was 0	The mean respiratory Rate (5 minutes after administration) in the intervention group was 0 (0 to 0)	–	37 (1 RCT)^†	⨁◯◯◯ VERY LOW^‡,§,‖
Glasgow Coma Scale (5 minutes after administration) (Glasgow Coma Scale)	The mean glasgow Coma Scale (5 minutes after administration) was 0	The mean glasgow Coma Scale (5 minutes after administration) in the intervention group was 0 (0 to 0)	–	27.5 (1 RCT)^†	⨁◯◯◯ VERY LOW^‡,§,‖
Arterial Blood Oxygen Saturation (5 minutes after administration)	The mean arterial Blood Oxygen Saturation (5 minutes after administration) was 0	The mean arterial Blood Oxygen Saturation (5 minutes after administration) in the intervention group was 0 (0 to 0)	–	189 (1 RCT)^†	⨁◯◯◯ VERY LOW^‡,‖
Median change in breaths	The mean median change in breaths was 0	The mean median change in breaths in the intervention group was 0 (0 to 0)	–	10 (1 observational study)^#	⨁◯◯◯ VERY LOW^‖,**
Median change in Glasgow Coma Scale	The mean median change in Glasgow Coma Scale was 0	The mean median change in Glasgow Coma Scale in the intervention group was 0 (0 to 0)	–	7 (1 observational study)^#	⨁◯◯◯ VERY LOW^‖,**
Positive clinical response (increase in respirations at least 6/min, GCS at least 6)	not pooled	not pooled	not pooled	154 (1 observational study)^††	⨁◯◯◯ VERY LOW^§,**
Mean response time (min)	The mean mean response time (min) was 0	The mean mean response time (min) in the intervention group was 0 (0 to 0)	–	21 (1 observational study)^††	⨁◯◯◯ VERY LOW^§,**
Proportion requiring second dose	not pooled	not pooled	not pooled	154 (1 observational study)^††	⨁◯◯◯ VERY LOW^§,**
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

^†Sabzghabaee from Iran.

^‡Unclear allocation, blinding, loss to follow-up. Analysis was not intention to treat with unclear post randomization exclusions.

^§Pre-fentanyl era.

^‖Small sample size with wide confidence intervals.

^#Merlin 2010 from US (New Jersey).

**Differences between groups at baseline without control for potential confounders.

^††Robertson 2009 from US (California).

Table 6. GRADE Table for Recommendation 3 - Intravenous (IV) vs. Intramuscular (IM)

Summary of findings:
Intramuscular naloxone compared to intravenous naloxone for suspected opioid poisoning
Patient or population: suspected opioid poisoning Setting: Prehospital Intervention: intramuscular naloxone Comparison: intravenous naloxone
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with intravenous naloxone	Risk with intramuscular naloxone
Clinical response (GCS ≥14 and RR ≥ 10/minute within 5 minutes of administration)	not pooled	not pooled	not pooled	591 (1 observational study)^†	⨁◯◯◯ VERY LOW^‡,§
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

^†Sporer 1996 from US (California).

^‡Differences between groups at baseline, potential confounding, outcome assessor not blinded to treatment.

^§Small sample size.

Table 7. GRADE Table for Recommendation 4 - Intravenous (IV) vs Subcutaneous (SQ)

Summary of findings:
Subcutaneous naloxone compared to intravenous naloxone for suspected opioid poisoning
Patient or population: suspected opioid poisoning Setting: Prehospital Intervention: subcutaneous naloxone Comparison: intravenous naloxone
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with intravenous naloxone	Risk with subcutaneous naloxone
Time from arrival to patient's side to administration	The mean time from arrival to patient's side to administration was 0	The mean time from arrival to patient's side to administration in the intervention group was 0 (0 to 0 )	–	9.7 (1 observational study)^†	⨁◯◯◯ VERY LOW^‡,§,‖
Time from administration to respiratory rate ≥10 breaths per minute	The mean time from administration to respiratory rate ≥10 breaths per minute was 0	The mean time from administration to respiratory rate ≥10 breaths per minute in the intervention group was 0 (0 to 0 )	–	9.3 (1 observational study)^†	⨁◯◯◯ VERY LOW^‡,§,‖
Time from arrival to patient's side to respiratory rate ≥10 breaths per minute	The mean time from arrival to patient's side to respiratory rate ≥10 breaths per minute was 0	The mean time from arrival to patient's side to respiratory rate ≥10 breaths per minute in the intervention group was 0 (0 to 0 )	–	18.9 (1 observational study)^†	⨁◯◯◯ VERY LOW^‡,§,‖
Proportion requiring redosing	not pooled	not pooled	not pooled	196 (1 observational study)^†	⨁◯◯◯ VERY LOW^š,§,‖
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

^†Wanger 1998 from Canada (Vanvouver, BC).

^‡Potential confounding, outcome assessor not blinded to treatment.

^§SC group redosed using IV naloxone.

^‖Small sample size with wide confidence intervals.

Chou R, Korthuis PT, McCarty D, Coffin P, Griffin J, Davis-O’Reilly C, Grusing S, Daya M. Management of suspected opioid overdose with naloxone by emergency medical services personnel [Internet]. Comparative Effectiveness Review No. 193. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2015-00009-I.) AHRQ Publication No. 17(18)-EHC025-EF. Rockville (MD): Agency for Healthcare Research and Quality; 2017 November. www.effectivehealthcare.ahrq.gov/reports/final.cfm. doi:10.23970/AHRQEPCCER193.

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