When emergency medical services personnel or laypeople treat opioid overdoses in the field, they increasingly are using naloxone to reverse overdose symptoms. But evidence is lacking on best practices for opioid overdose management outside of the hospital setting, including optimal dose and route of administration.
That's according to a systematic evidence review(annals.org) published online Nov. 28 in Annals of Internal Medicine.
Researchers with the Agency for Healthcare Research and Quality reviewed 13 published studies to determine how the route of administration and dosing of naloxone in an out-of-hospital setting affected mortality, reversal of overdose symptoms and harms, as well as the need for transport to a health care facility after reversal of overdose.
What they found was that higher-concentration intranasal naloxone had efficacy similar to that of intramuscular naloxone in reversing overdose symptoms and demonstrated no difference in adverse events.
- A systematic evidence review recently published in Annals of Internal Medicine examined use of naloxone to treat opioid overdoses in the field.
- Researchers with the Agency for Healthcare Research and Quality reviewed 13 published studies to determine how the route of administration and dosing of naloxone in an out-of-hospital setting affected mortality, reversal of overdose symptoms and harms, as well as the need for transport to a health care facility after reversal of overdose.
- Findings included that higher-concentration intranasal naloxone had efficacy similar to that of intramuscular naloxone in reversing overdose symptoms and demonstrated no difference in adverse events.
Additionally, after naloxone had been used to reverse overdoses, no serious harms associated with then not going to the hospital were identified.
Naloxone Dosage, Formulation
According to the evidence review, no study directly compared different naloxone doses or formulations administered by the same route. Instead, comparisons involving dose or formulation were made only indirectly based on studies that compared different routes of administration.
For example, in two randomized controlled trials (RCTs) that compared intranasal with intramuscular naloxone, the intranasal concentration used in one trial was 2 mg/5 mL, whereas the intranasal concentration used in the second trial was 2 mg/mL. The total dose administered (2 mg) was the same in both trials.
The authors said the different concentrations might explain the variance in results seen in the two trials, given a maximum volume of 0.5 mL absorbed by each nostril.
"Therefore, the effective (bioavailable) dose of naloxone was probably lower in the trial that used a lower-concentration formulation than in the trial that used a higher-concentration formulation," the study said.
It should be noted that no study evaluated the newly FDA-approved, highly concentrated reformulations of naloxone (2 mg or 4 mg/0.1 mL).
In other studies involving intranasal versus intravenous naloxone, the doses and formulations varied or were not well-described, resulting in an inability to pinpoint comparative effects.
One RCT compared intranasal naloxone (0.4 mg/2 mL, at a dose of 0.2 mg/nostril) versus intravenous naloxone (0.4 mg), but two observational studies didn't specify the concentration of the intranasal formulation (2 mg dose), and the intravenous dose ranged from 0.4 mg to 2.0 mg or wasn't reported.
"Therefore, it was not possible to reach reliable conclusions about the comparative effects of different naloxone doses and formulations from these studies," the authors said.
In addition, no study compared the benefits and harms of titration of naloxone until resumption of sufficient spontaneous respiratory effort versus naloxone titration until return to consciousness.
One RCT defined a response not requiring repeated administration as an improvement in respiratory rate of at least 10 breaths per minute and a Glasgow Coma Scale score of 13 or greater. Other studies comparing routes of administration didn't specify titration targets.
As for timing of repeated doses of naloxone, no study compared the benefits and harms of different timing. Among five studies comparing routes of administration, timing of repeated doses was one to two minutes in one study and five to 10 minutes in the others.
"Because of other differences between trials (such as different doses and formulations, routes of administration and study design), it was not possible to assess the effects of different redosing intervals on effectiveness," the study said.
Transportation After Naloxone Administration
The review's authors said no study compared outcomes between patients who were transported to a hospital after successful reversal of opioid overdose with naloxone and those who were not.
Six studies reported outcomes for patients not transported to a health care facility after successful naloxone treatment, although none of the studies said how long patients were observed after successful reversal of overdose. These studies also were rated as having high risk of bias because of their uncontrolled design, failure to blind outcome assessors to exposure status and failure to report missing data.
"The uncontrolled design makes interpretation of findings difficult, given likely differences between persons who decline transport and those who are transported," the authors said.
The researchers concluded that "although naloxone is generally effective at reversing suspected opioid overdose, evidence to inform optimal management of suspected overdose with naloxone in out-of-hospital settings is limited."
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