Introduction

Nature and Burden of Opioid Overdose

Addiction and overdoses associated with prescription and illicit opioids have been characterized by the U.S. Department of Health and Human Services as a national crisis.¹ Since 2000, the rate of overdose deaths involving opioids has increased four-fold.^2,3 Drug overdose deaths are now the leading cause of injury-related death in the United States.⁴ Overdose deaths due to opioids occur as a result of their central nervous system effects, which cause respiratory depression that can progress to cardiac arrest if untreated. In 2015, the number of drug overdose deaths involving prescription or illicit opioids exceeded 33,000, the highest number on record.³ The strongest risk factor for an opioid overdose death is a prior overdose event. Other risk factors include concomitant use of other medications and substances with central nervous system depressant effects, recent abstinence (due to decreased tolerance to opioids upon re-exposure), higher doses of opioids, obtaining opioids from multiple providers or pharmacies, presence of comorbid conditions such as sleep apnea or other respiratory disease, and genetic predisposition to the respiratory depressant effects of opioids.^5–10 Of recent concern is whether dosing guidelines are sufficient for reversing overdose related to highly potent synthetic opioids (e.g. fentanyl and fentanyl analogues).^3,11–15 In addition, although overdoses with opioids often involve other medications and substances with respiratory depressant effects, naloxone has minimal benefit for other types of overdoses. Children in households with an adult who is prescribed opioids are also at risk for overdose.^16,17 Opioid overdoses can have serious adverse health consequences (e.g., hypoxic brain injury, aspiration, seizure), even when not fatal. Although difficult to measure, the ratio of nonfatal to fatal overdoses has been estimated to range from 7.5:1 to 30:1.^18,19

Field Treatment of Suspected Opioid Overdose With Naloxone

Naloxone is an opioid antagonist that was first approved in 1971 to rapidly counteract the central nervous system (CNS) and respiratory depressant effects of opioids, potentially preventing fatal overdose.²⁰ Naloxone can be administered by the intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (IN), endotracheal (ET), nebulized/inhalational, buccal, or sublingual routes.²¹ The U.S. Food and Drug Administration (FDA) approved a handheld naloxone IM or SC auto-injector in 2014²² and a new IN formulation and delivery device in 2015;²³ both administer a consistent preset dose and were designed for ease of use even by individuals with limited or no health care training. With IN administration using a preloaded device, there is no risk of needle stick injury. In addition to administration by clinical personnel, naloxone also is associated with decreased risk of opioid overdose when distributed in community-based programs.^24–26 Naloxone has been shown to be effective for reversal of opioid overdose across various routes of administration and doses.^20,27

Naloxone administration may precipitate withdrawal symptoms in chronic opioid users.²⁸ Risk of naloxone withdrawal depends on factors such as the degree of physical dependence, dose of opioid, and dose of naloxone. Reported rates of withdrawal following naloxone administration range from 7 to 46 percent.²⁹ While uncomfortable, withdrawal symptoms are generally not serious or life-threatening and generally short-lived. Post withdrawal agitation following naloxone administration may also put the person administering the naloxone at increased risk for injury.^30,31 Withdrawal symptoms may be more severe with use of IV naloxone and are less likely to occur or minimized in severity by using the lowest effective doses and dose titration. ^{20,28 20,28 20,28} The duration of action of naloxone is 20 to 90 minutes, or shorter than many opioids. ^{20 20 20}

Emergency medical services (EMS) personnel are often involved in management of potential opioid overdoses. When responding to opioid overdoses, early intervention is critical to prevent death and other complications of opioid overdose.³² Airway management and continuous assessment of oxygenation and ventilation, along with administration of naloxone, is the standard of care for EMS personnel treating suspected opioid overdoses.³³ According to the National EMS Information System database, the number of EMS encounters for suspected opioid overdose has increased, with nearly 160,000 doses of naloxone administered by EMS personnel in 2014.³⁴ Regulations vary, however, with regard to whether EMS personnel with different levels of training are permitted to administer naloxone. In order of increasing level of training, EMS personnel are commonly classified as emergency medical responders (EMRs), emergency medical technicians (EMTs), intermediate/advanced EMTs, and paramedics (in most states, the intermediate EMT classification has been replaced by advanced EMTs).³⁵ Naloxone administration is not currently within the National EMS Scope of Practice Model for EMTs and EMRs, which was last updated in 2007,³⁵ prior to the introduction of newer naloxone formulations and availability of newer evidence on the benefits of field use of naloxone. However, each state can independently amend its EMS scope of practice. A recent systematic review³⁶ of U.S. laws, regulations, and policies found that all jurisdictions permitted paramedics and 48 permitted intermediate/advanced EMTs to administer naloxone. Fewer jurisdictions permitted basic life support personnel to administer naloxone, which may contribute to disparities in areas in which more care is provided by EMRs and EMTs.³⁷ One study found that among 724 patients treated in out-of-hospital settings by Basic Life Support EMS personnel and transported to a hospital, fewer than 10 percent of patients received additional doses of naloxone in the ED; there was one death.³⁸

Although a number of recommendations, guidelines, and protocols are available to inform out-of-hospital management of opioid overdose patients, including naloxone use, guidance varies across these documents, and there are uncertainties in a number of areas.^39–41 A review of naloxone dosing recommendations found that 48 percent recommended a starting dose of 0.05 mg or lower, 16 percent recommended 0.1 mg, and 36 percent recommended 0.4 or 0.5 mg.⁴² The 2015 American Heart Association (AHA) guideline update for cardiopulmonary resuscitation and emergency cardiovascular care notes that the ideal dose of naloxone is not known; an empiric starting dose of 0.04 to 0.4 mg IV or IM is recommended to avoid provoking severe opioid withdrawal and to allow for a range of doses depending on the clinical scenario, with repeat doses or dose escalation to 2 mg if the initial response is inadequate.³⁹ The naloxone auto-injector approved by the FDA in 2014 administered a dose of 0.4 mg.²² However, a 2 mg auto-injector was approved in 2016 and the 0.4 mg dose is no longer being manufactured.⁴³ For IN naloxone, the AHA guideline notes that most studies used off-label dosing of 2 mg in 2 mL of solution via an atomizer, with the dose repeated in 3 to 5 minutes if necessary. Despite clinical experience suggesting effectiveness of such off-label IN administration, potential concerns include inadequately characterized pharmacokinetics, low bioavailability, high rates of administration errors, and inadequate dosing for overdoses due to potent opioids.^44,45 In 2015, the FDA approved a reformulation of IN naloxone at a dose of 4 mg in a highly-concentrated solution of 0.1 mL;⁴⁶ a 2 mg/0.1 ml formulation was approved in 2017.⁴⁷ Concentrated solutions may be important for optimal IN administration due to a low rate of absorption (a high proportion of IN naloxone is swallowed and inert) with low bioavailability; a maximum of ≤0.5 mL can be effectively delivered per nostril. Another formulation of IN naloxone did not receive FDA approval in 2015; it delivered a total of 1.8 mg of naloxone, which was determined by the FDA to not fully meet the equivalent FDA threshold dose (0.4 mg IM naloxone).⁴⁸

Therefore, there are uncertainties regarding the optimal route of naloxone administration, the optimal dose for different routes of administration, optimal dosing strategies, and appropriate training levels for EMS personnel permitted to administer naloxone. Of recent concern is whether current dosing guidelines are sufficient for reversing overdose related to highly potent synthetic opioids.⁴⁹ Data suggest that the proportion of patients who receive multiple naloxone administrations by EMS personnel increased from 14 percent in 2012 to 18 percent in 2015.⁵⁰ The increase may be related to a higher proportion of overdoses involving highly potent opioids, higher doses of opioids, or sustained-release or long-acting opioids. There is also uncertainty regarding the optimal timing of repeat naloxone dosing, as well as the optimal dose of naloxone that should be administered by various routes. Another important question is whether patients should be dosed until they achieve sufficient spontaneous respiration or until they return to full consciousness. Although dosing to full consciousness might reduce the likelihood of recurrence of overdose symptoms or complications related to decreased level of consciousness (e.g., aspiration or upper airway obstruction), a potential trade-off is increased likelihood or severity of withdrawal symptoms or refusal to be transported to a health care facility. A related question is whether mandatory hospital transport is medically necessary following successful naloxone treatment of opioid overdose,⁵¹ and whether there may be additional benefits of hospital transport in addition to those related to the current overdose episode, such as increased likelihood of linkage of care for treatment for opioid use disorder, alerting prescribers if the involved opioids were prescribed, and decreased risk of subsequent overdose.

Rationale for Review

The purpose of this systematic review is to synthesize the evidence on naloxone route of administration and dosing for suspected opioid overdose in out-of-hospital settings, and on the need for transport to a hospital following successful opioid overdose reversal with naloxone. The review is intended to inform development of evidence-based guidelines on EMS management of suspected opioid overdose with naloxone and potentially inform an update to the National EMS Scope of Practice Model regarding naloxone use across EMS training levels. Therefore, the review focuses on studies of naloxone administration by EMS personnel. Because studies of naloxone administration by non-EMS first responders and laypeople may also have some applicability for EMS administration, we also included studies of naloxone administration by non-EMS personnel.

Scope and Key Questions

The report addresses the following Key Questions.

Key Question 1.

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?

1a.

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?

Key Question 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?

Key Question 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?

Key Question 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 versus nontransport?

The research questions used to guide this review were initially developed by the National Highway Traffic Safety Administration (NHTSA) and revised with input from a Technical Expert Panel (TEP). The Key Questions focus on the comparative benefits and harms of alternative routes of administration, dose, and dosing strategies for naloxone administered for suspected opioid overdose in the field, and benefits and harms of transport to a health care facility versus nontransport after successful treatment of suspected opioid overdose with naloxone.

The analytic framework (Figure 1) shows the target population, interventions, and health outcomes examined; the Key Questions are numbered and indicated in the framework. We focused on use of IN, IM, and IV naloxone; these are the formulations of naloxone most commonly used for reversal of suspected opioid overdose in the field by EMS personnel. Key Question 1 addresses benefits and harms of different routes of naloxone administration, Key Question 1a addresses benefits and harms of different doses of naloxone administration, Key Question 2 addresses benefits and harms of dosing until the patient resumes sufficient spontaneous respiratory effort but is not necessarily fully conscious versus until the patient regains full consciousness, Key Question 3 addresses benefits and harms of differences in timing of repeat dosing, and Key Question 4 addresses benefits and harms of transporting patients following successful reversal of naloxone overdose versus nontransport. Although the focus of the review was on use of naloxone by field personnel, we also included studies of naloxone administration in out-of-hospital settings by non-EMS personnel (e.g., police or other laypeople), which could help inform optimal dosing strategies by EMS personnel with additional training.

Analytic Framework

Figure 1Analytic framework

*

Patients with confirmed or suspected opioid overdose who exhibit altered mental status, miosis, or respiratory distress and who are treated in the out-of-hospital setting by emergency medical services personnel

†

Administration of naloxone hydrochloride via the nasal, intravenous, intramuscular, or subcutaneous injection (including the naloxone auto-injector)

‡

Key Question 1 addresses comparisons involving route of administration and dose; Key Question 2 addresses comparisons involving dose titration to varying degrees of return of consciousness (intermediate outcome)