Objectives:

To compare different routes, doses, and dosing strategies of naloxone administration for suspected opioid overdose by emergency medical services (EMS) personnel in field settings, and to compare effects of transport to a health care facility versus nontransport following successful reversal of opioid overdose with naloxone.

Methods:

Four databases were searched through September 2017. Additional studies were identified from reference lists and technical experts. We included randomized controlled trials (RCTs) and cohort studies comparing different naloxone routes of administration, doses, or dosing strategies and on effects of transport or nontransport following successful reversal of opioid overdose with naloxone. Two investigators independently applied prespecified criteria to rate study quality. The strength of evidence was determined based on the overall risk of bias, consistency, directness, precision, and reporting bias. Main outcomes were mortality, reversal of opioid overdose symptoms, time to reversal of symptoms, recurrence of overdose symptoms, and harms.

Results:

Thirteen studies met inclusion criteria. Three RCTs and four cohort studies compared different routes of administration. Two trials compared intranasal (IN) with intramuscular (IM) naloxone administration (strength of evidence [SOE] for all outcomes: low). While 2 mg of a higher concentration formulation of IN naloxone (2 mg/1 mL) is similar in efficacy to 2 mg of IM naloxone, 2 mg of a lower concentration formulation of IN naloxone (2 mg/5 mL) is less effective than the same dose IM but associated with decreased risk of agitation and/or irritation. The 2 mg/5 mL formulation of IN naloxone studied in this trial is lower than concentrations used in the United States. In both trials, IN naloxone was associated with increased likelihood of rescue naloxone use.

Although one RCT and two observational studies evaluated intravenous (IV) versus IN naloxone, evidence was insufficient to determine comparative benefits and harms because of methodological limitations and poor applicability to U.S. EMS settings (SOE: insufficient). There was insufficient evidence from two observational studies to compare parenteral routes of administration (IM, IV, or subcutaneous).

No study compared outcomes of patients transported versus not transported following successful reversal of opioid overdose with naloxone. Six studies reported low rates of deaths and serious adverse events (0% to 1.25%) in patients not transported to a hospital after successful naloxone treatment but used an uncontrolled design and had other methodological limitations (SOE: insufficient).

Limitations:

Few studies met inclusion criteria, all studies had methodological limitations, and no study evaluated naloxone auto-injectors or IN naloxone formulations recently approved by the U.S. Food and Drug Administration (FDA).

Conclusions:

Low-strength evidence suggested that higher concentration IN naloxone (2 mg/1 mL) is similar in efficacy to IM naloxone (2 mg), with no difference in adverse events. Research is needed on the comparative effectiveness of the FDA-approved naloxone auto-injectors (0.4 mg and 2 mg) and highly concentrated (4 mg/0.1 mL and 2 mg/0.1 mL) IN naloxone reformulation, different doses, and dosing strategies. Uncontrolled studies suggest that nontransport of patients following successful naloxone reversal of overdose is associated with a low rate of serious harms, but patients were probably at low risk for such events, and no study evaluated risk of transport versus nontransport.