The need for multiple naloxone administrations for opioid overdose reversals: A review of the literature

Figures & data

Figure 1. Article selection schema.

Table 1. Summary table of published studies on MNA.

Author, year	Study design	Analysis timeframe	Sample size	Study population	Proportion of cases with ≥2 doses of naloxone administered	Total dose administered
Faul, 2017^16	Retrospective database analysis of the National Emergency Medical Service Information Systems (NEMSIS) database	2012-2015	Number of patients who received naloxone by year 2012 N = 95,012 2013 N = 112,844 2014 N = 127,956 2015 N = 173,016	Individuals who received naloxone via EMS	Percentage of individuals receiving ≥2 doses of naloxone from EMS personnel: 2012:   13,765/95,012 (14.49%, 95% CI: 14.26–14.71%) 2013:   16,281/112,844 (14.91%, 95% CI: 14.71–15.11%) 2014:   20,884/127,956 (16.32%, 95% CI: 16.12–16.52%) 2015:   31,554/173,016 (18.24%, 95% CI: 18.06–18.42%) Overall, MNA increased 25.8% from 2012 to 2015	NR
Geiger, 2019^17	Retrospective database analysis of the NEMSIS database	2013–2016	Number of patients who received naloxone by year 2013 N = 107,666 2014 N = 122,506 2015 N = 166,002 2016 N = 206,354	Individuals who received naloxone via EMS	Significant increases (all p < .001) in percentage of individuals receiving ≥2 doses of naloxone from EMS personnel: 2013: 15% 2014: 16.5% 2015: 18.1% 2016: 21.4%	NR
Klebacher, 2016^18	Retrospective chart review of patients with suspected opioid overdose, treated with intranasal naloxone, based on EMR charts of largest provider of EMS services in New Jersey	April 2014–June 2016	N = 2,166	Individuals >17 years of age with suspected opioid overdose treated with intranasal dose of naloxone and subsequently managed by EMTs	195/2,166 (9%) received ≥2 naloxone doses 1971/2,216 (91%) experienced complete resolution with 1 naloxone dose • 53/2,166 (2.4%) of patients received 3 naloxone doses	NR
Fidacaro, 2019^19	A retrospective observational study of individuals receiving prehospital naloxone and transported to an inner-city ED in Camden, NJ	January 2, 2016–December 31, 2016	Total N = 473	Adults (≥18 years of age) treated with naloxone in a prehospital setting and transported by an inner-city hospital-based EMS to it’s affiliated ED	178/473 (38%) received multiple doses of naloxone in the prehospital setting • 34/473 (7%) received a repeat dose in the Emergency Department setting	NR
Purssell, 2020^20	A retrospective matched cohort study of opioid overdose cases treated in 2 urban Emergency Departments (ED) Patients who were administered low dose naloxone (LDN, ≤0.15 mg) were matched on a 1:4 ratio to patients who were administered high dose naloxone (HDN, >0.15 mg), based on initial respiratory rate	January 1, 2013 to December 31, 2017	Total N = 379 HDN n = 299 LDN n = 80	Patients with a presenting compliant of opioid overdose and were administered naloxone in the ED or administered naloxone by a layperson, paramedic or emergency personnel	199/379 (53%) received ≥2 doses of naloxone overall 1 naloxone dose used: 180 (48%) 2 doses used: 91 (24%) 3 doses used: 59 (16%) 4 doses used: 22 (6%) 5+ doses used: 27 (7%)	Mean (SD) naloxone dose for all subjects:   0.85 (0.76) Mean (SD) naloxone dose for all subjects until reversal: 0.58 (0.46) Mean (SD) naloxone dose for all subjects post reversal: 0.26 (0.44)
Maloney, 2020^21	A retrospective observational chart review of patients receiving prehospital naloxone and transported to Stony Brook University Hospital (SBUH), a suburban academic tertiary care center	January 1, 2014 to December 31, 2017	Total N = 513	Adults (≥18 years of age) treated with naloxone in a prehospital setting and transported by an ambulance to SBUH ED	160/513 (31%) received ≥2 doses of naloxone in the prehospital setting 1 naloxone dose used: 353/513 (69%) 2 doses used: 140/513 (27%) 3 doses used: 20/513 (4%)   41/76 (54%) received multiple doses of naloxone in the ED 19/76 (25%) were started on a naloxone infusion.	Median (range) of prehospital naloxone: 3 mg (2–3)
Krotulski, 2021^22	A pilot study of patients presenting to an urban tertiary care ED after a non-fatal opioid overdose.	June 2017 to December 2018	N = 20	Adult patients presenting to the ED who arrived after naloxone administration and who required venipuncture or intravenous access as part of clinical care.	10/20 (50%) received ≥2 doses of naloxone 1 naloxone dose used: 10/20 (50%) 2 doses used: 7/20 (35%) 3 doses used: 3/20 (15%)	Median (IQR) of calculated naloxone dose: 4 mg (2–5.1)
Bell, 2019^23	Prospective cross-sectional interviews of participants in the Prevention Point Pittsburgh (PPP) program. PPP is a community-based syringe access program that distributes naloxone to people who use drugs	January 2013–December 2016	N = 1,072	Participants in the PPP program who had used naloxone	462/1,072 (43%) had ≥2 naloxone doses administered 383/1,072 (35.7%) had 2 naloxone doses administered 47/1,072 (4.4%) had 3 naloxone doses administered 32/1,072 (3%) had 4 or more naloxone doses administered *no significant differences between any 4 years (2013–2016) on the average number of doses per overdose mean (SD) dose per reversal: 1.56 (0.93)	NR
Avetian, 2018^24	Telephone interviews with contacts of organizations that received 4 mg naloxone nasal spray to retrospectively collect data on circumstances regarding use of naloxone fo opioid overdose reversals	April–August 2016	Organizations contributing data N = 40 Opioid overdose reversals N = 261 Cases reporting doses administered N = 254	Participating organizations included law enforcement, county government, health departments, EMS, advocacy, community outreach and harm reduction organizations, volunteers, shelters and pharmacy service centers, located in CA, IN, ME, MD, NM, NC, & PA	89/254 (35%) had ≥2 naloxone doses administered 83/254 (33%) had 2 naloxone doses administered 5/254 (2%) had 3 naloxone doses administered • 1/254 (0.4%) had 4 naloxone doses administered	NR
Katzman, 2019^25	Prospective, 6-month cohort study to identify the characteristics of individuals participating in an opioid treatment program for OUD who used take-home naloxone to perform ≥1 opioid overdose reversal	April 2016–October 2016	Total N = 215 Used naloxone n = 44 Did not use naloxone n = 207	Adult participants being treated at University of New Mexico Addiction & Substance Abuse Program (ASAP)	37/65 (57%) received ≥2 doses of naloxone 1 naloxone dose used: 28 (43%) 2 doses used: 35 (54%) • 3 doses used: 2 (3%)	NR
Somerville, 2017^26	1) in-person interviews with individuals with opioid use disorder and 2) Retrospective medical examiner chart abstraction	Interviews: April 2016 Chart abstraction: Deaths occurred between October 2014–March 2015	Interviews: N = 64 Chart abstraction: N = 196	Interviews: Individuals ≥18 years of age who used illicit opioids in past 12 months who witnessed or experienced an opioid overdose in past 5 months Chart abstraction: Opioid overdose deaths occurring in 3 Massachusetts counties	• 40/48 respondents (83%) reported that ≥2 naloxone doses per suspected fentanyl overdose were used before person responded.	NR
Mahonski, 2019^27	A retrospective study of naloxone administrations from prepacked naloxone kits (PNK) reported to the Maryland Poison Control Center	January 1, 2015 to October 15, 2017	N = 1139 PNK administrations 2015 n = 121 2016 n = 433 2017 n = 585	Suspected opioid overdoses cases where either a layperson or law enforcement officer administered the naloxone from a prepacked naloxone kit	Percentage of individuals receiving ≥2 doses of naloxone: 2015: 19/121 (16%) 2016: 82/433 (19%) 2017: 118/585 (20%) Overall, MNA increased 25% from 2015 to 2017	Mean (median) dose increased significantly from 2015 to 2017 (p < .0001): 2015: 2.12 mg (2 mg) 2016: 2.54 mg (NR) 2017: 3.63 (4 mg)
Parkin, 2021^28	A qualitative interview study subsumed within a larger randomized trial evaluating 2 different overdose prevention training approaches in the NYC metropolitan area.	2014–2019	N = 56 Overdose events where > 1 dose of naloxone was administered for a opioid overdose event: N = 24	Individuals enrolled in the larger randomized trial that had witnessed an opioid overdose and had direct or indirect participation in an opioid overdose reversal using a take home naloxone kit in the past 3 months.	24/56 (43%) of overdose events where ≥2 doses of naloxone were administered Of overdose events where > 1 naloxone dose was administered, 10 (42%) involved administration of 2 doses of naloxone in under 2 min, outside of the recommended OEND response interval of 2–4 min.	NR
Schneider, 2021^29	A mixed methods, cross-sectional study design of individuals who used non-prescription opioids in Anne Arundel County, MD	November 2019–March 2020	Total N = 171 Received naloxone in past 6 months n = 61 Did not receive naloxone in past 6 months n = 110	Adults (≥18 years of age) who used non-prescription opioids in the past 6 months	54/61 (89%) received ≥2 doses of naloxone 1 naloxone dose used: 7 (12%) 2 doses used: 44 (72%) 3 doses used: 7 (12%) 4+ doses used: 3 (5%) Of those who had administered naloxone in the past 6 months, 23/29 (79%) reported that more than 2 doses were needed to reverse the overdose.	NR
Carpenter, 2020^31	Retrospective chart review of patients from a single Emergency Department (ED) and affiliated emergency medical services agency	January 2017–June 2018	Total N = 121 Opiates n = 28 Fentanyl n = 23 Opiates + fentanyl n = 70	Individuals with a diagnosis of opioid overdose, abuse or toxicity and had a urine drug screen (UDS) performed during hospitalization that was positive for opiates, fentanyl or both.	NR	Total naloxone dose for all subjects (median, range): 0.80 (0.18–5.20) Total naloxone dose for fentanyl (median, range): 0.80 (0.18–5.20) Total naloxone dose for opiates only (median, range): 0.58 (0.18–2.00) Total naloxone dose for opiates + fentanyl (median, range): 0.80 (0.18–3.60) *No significant differences in total naloxone dose administered between groups
Marco, 2018^32	Prospective survey of patients in the ED after an unintentional opioid overdose	July 2016–July 2017	N = 89	All adult individuals (≥18 years) presenting in the Miami Valley Hospital ED with an unintentional opioid overdose	NR	44/89 (49.4%) were administered 6 mg total naloxone dose or higher • The median prehospital dose was 4 mg (range: 0–26 mg)
Massey, 2017^30	Retrospective case series of an opioid outbreak in Cabell County, West Virginia	August 2016	N = 20 Probable cases n = 12 Confirmed cases n = 8	Individuals identified as probable opioid overdose cases within a 53-hour period in Cabell County, WV	• 6/20 (30%) received ≥2 naloxone doses	5 of 6 were IV administrations of 0.4 mg per dose
Sutter, 2017^33	Case series of 18 patients presenting with exaggerated opioid toxicity at a single hospital over an 8-day period	March 2016	N = 18	Individuals presenting to a single urban academic ED with symptoms of severe opioid overdose	NR	17/18 patients required boluses of naloxone and 4 required prolonged naloxone infusions (26–39 h)
Solomon, 2017^34	A case study of 1 female presenting to ED with severe opioid toxicity	N/A	N = 1	Adult female presented at large urban Ohio ED	NR	17 mg total naloxone (divided doses) were administered before patient returned to consciousness

NR: Not reported.

Figure 2. Proportion of individuals receiving ≥2 naloxone doses for opioid overdose reversal by study.

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