Intranasal Naloxone for Opioid Overdose

Opioid overdose deaths in the United States (US) are a public health emergency, exceeding 80,000 in 2021.¹ Individuals with opioid use disorder (OUD) and other people who use prescribed and non-prescribed opioids are at risk for opioid overdose. Fentanyl contamination of other substances, such as stimulants and benzodiazepines, has been increasingly described. Naloxone is a competitive opioid receptor antagonist that can reverse symptoms of opioid intoxication and overdose by displacing opioids from μ-opioid receptors. In 2015, the Food & Drug Administration (FDA) approved a 4mg/0.1mg intranasal naloxone formulation for administration by laypeople, which is the standard-of-care in community overdose response. In March 2023, the FDA approved 4mg/0.1mL intranasal naloxone for over the counter (OTC) use, and in July 2023, a generic 4mg/0.1mL product and a 3mg/0.1 mL formulation for OTC use.

Indications for Naloxone Administration

Naloxone administration is recommended when an individual experiences signs and symptoms of opioid overdose: miosis, sedation or coma, respiratory depression, abnormal respirations (e.g., gurgling or snoring sounds), cool or clammy skin, and cyanosis. Typically administered as a single 4mg/0.1mL intranasal dose, naloxone may have a shorter duration of action than opioids. In addition to administering naloxone, responders should activate emergency services. Responders should also provide rescue breaths or chest compressions, consistent with their level of training, comfort, and available equipment. If spontaneous breathing has not been restored in three minutes, an additional naloxone dose should be administered.

Naloxone Efficacy in Reversing Opioid Overdose

Intranasal naloxone at the FDA-approved OTC doses has not been studied in randomized clinical trials due to the ethics of withholding overdose treatment. Prior randomized trials comparing lower doses and less concentrated formulations to intramuscular (IM) administration showed efficacy in opioid overdose reversal, but lower efficacy compared to IM administration. Subsequent studies showed that higher intranasal doses were needed to match bioavailability of IM administration. The 4mg/0.1mL and 3mg/0.1mL intranasal formulations have demonstrated appropriate bioavailability.

Despite the lack of clinical trial data, observational and quasi-experimental studies demonstrate that community naloxone distribution is associated with lower rates of opioid overdose fatality.² A 2015 meta-analysis of four epidemiologic studies including 66 overdose events evaluating bystander naloxone administration demonstrated that bystander naloxone administration was associated with increased odds of overdose recovery (OR 8.58, 95% CI 3.90-13.25) compared to no naloxone administration.³

Walley and colleagues evaluated the impact of overdose education and naloxone distribution programs in Massachusetts, which trained 2912 potential bystanders including people who use opioids, family and friends, and social service providers. Compared to communities that did not implement naloxone, those that enrolled 1-100 people per 100,000 population and >100 people per 100,000 population had significant reductions in opioid overdose death rates after adjusting for demographics, addiction treatment engagement, and high-risk opioid prescriptions (adjusted rate ratios 0.73, 95% CI 0.57-0.91 and 0.54, 95% CI 0.39-0.76, respectively).⁴

Patients on long-term opioid treatment for chronic pain also benefit from naloxone co-prescribing. A non-randomized study of 1,985 adults on long-term opioid therapy showed that those who received a naloxone prescription had 63% fewer opioid-related ED visits per month over the following year (IRR=0.37, 95% CI 0.22–0.64, P<0.001) compared to patients who did not receive naloxone.⁵

Naloxone is a safe and effective medication to prevent opioid overdose death which meets the FDA’s four criteria for OTC approval: its benefits outweigh risks, it treats a condition that can be identified by laypeople, it has a low potential for misuse, and it can be labeled in a way that allows laypeople to administer it properly.

Naloxone Safety

Intranasal naloxone administration in the setting of possible opioid overdose is safe and effective. Among people without recent opioid exposure, naloxone is not expected to have any effect; therefore, it can be administered without delay.

Naloxone administration during opioid overdose is of minimal clinical risk, a risk outweighed by the benefit of preventing opioid overdose fatalities. The potential risks of naloxone administration are rarely life-threatening and include precipitated opioid withdrawal symptoms such as nausea, vomiting, agitation, tachycardia, and hypertension. More serious complications, including cardiac events in the setting of catecholamine surge and pulmonary edema are rare and, in the latter case, difficult to distinguish from opioid-induced pulmonary edema.⁶ Side effects are mitigated by using clinically appropriate doses (i.e., by not administering more naloxone than necessary to restore breathing) and activating emergency services for transport to supportive care.

Who Should Carry Naloxone?

Anyone at risk for experiencing opioid overdose should carry naloxone, including people with OUD or a history of prior opioid overdose; people using other substances that may be contaminated with opioids; and people using non-prescribed opioids, opioids and central nervous system depressants (e.g., benzodiazepines) concurrently, or prescribed opioids for chronic pain. Among those taking opioids for chronic pain, the Centers for Disease Control and Prevention recommends naloxone co-prescribing when daily morphine milligram equivalents meet or exceed 50mg, though many health systems have implemented universal co-prescribing.⁷

People who may witness opioid overdose should also carry naloxone. OUD prevalence is estimated to approach 5% of the population in some parts of the US; the role for naloxone use by bystanders is accordingly broad.⁸ Friends and family of people who use substances, first responders, and those working in settings with public bathrooms (e.g. public libraries), which are common sites of injection drug use in jurisdictions without supervised consumption spaces, all benefit from ready naloxone access.

Which Access Barriers does OTC Naloxone Address?

OTC naloxone addresses barriers related to stigma; people who may feel uncomfortable or have experienced mistreatment requesting naloxone from their clinician, utilizing harm reduction services, or requesting naloxone from a pharmacist under a standing order may feel more comfortable purchasing OTC naloxone. Naloxone’s OTC status may also reduce stigma, conveying the message that naloxone is safe, effective, and should be readily available.

OTC naloxone also improves availability by expanding access beyond commercial pharmacies to gas stations, grocery stores, other businesses, and via online sale. Such expansion has significant implications for areas with inadequate naloxone access, including large parts of the rural US.

Which Barriers to Naloxone Access and Uncertainties Remain?

The out-of-pocket cost of OTC intranasal naloxone, while not yet known, is expected to remain a barrier. The approval of a generic product and a second OTC dose formulation may reduce cost over time. The impact of OTC naloxone on pharmacy sales is difficult to estimate; it has been projected to drive a 15% to 179% increase in the quantity of naloxone sold at pharmacies.⁹ This increase raises the possibility of drug shortages, including shortages impacting community programs involved in direct naloxone distribution to individuals at highest risk.

Advocates have also raised concern that OTC status could paradoxically increase cost for people who currently access naloxone via a prescription; for example, if insurance providers do not cover the OTC formulation and/or reduce coverage of other formulations.¹⁰

Equity in access is another potential concern. It is unclear whether all pharmacies, including those serving historically marginalized populations, will stock OTC naloxone. Pharmacy decisions on naloxone storage – for example, in the aisles, or behind the counter, requiring a conversation with a staff member or pharmacist – will impact the degree to which OTC status mitigates the stigma of requesting naloxone.

Additionally, the optimal dose of intranasal naloxone in the fentanyl era remains uncertain. While approved OTC formulations achieve appropriate bioavailability, there have been reports of fentanyl overdose events that required multiple naloxone doses. There are also harms associated with administering too high a dose of naloxone, including severe precipitated opioid withdrawal, refusal of acute care, and avoidance of future naloxone administration.

The question of dose is complicated by rising rates of polysubstance-involved overdoses, which include non-opioid substances (e.g., xylazine) that are not reversed by an opioid receptor antagonist. Higher-dose prescription intranasal naloxone formulations are now available, but the FDA has determined that there are insufficient data to support their safety in the OTC setting. While the optimal intranasal naloxone dose warrants further study, the currently available formulations are safe and effective, even in the fentanyl era.

Conclusions

Intranasal naloxone is safe and effective in opioid overdose reversal. Providing naloxone to people who may experience or witness opioid overdose is supported by guidelines, and OTC approval recognizes the safety of intranasal naloxone, its efficacy when administered by laypeople, and the urgency of expanding access. Amidst uncertainties about the pricing of OTC naloxone, physicians and other licensed independent practitioners should continue to prescribe naloxone to those who may benefit as a standard part of their practice.