In contrast to direct opiate agonists, which elicit opiate withdrawal symptoms when discontinued in opiate-tolerant people, no evidence indicates the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood, but studies suggest it functions to produce withdrawal symptoms by competing for opioid receptors within the brain (a competitive antagonist, not a direct agonist), thereby preventing the action of both endogenous and xenobiotic opioids on these receptors without directly producing any effects itself.A single administration of naloxone at a relatively high dose of 2 mg by intravenous injection has been found to produce brain MOR blockade of 80% at 5 minutes, 47% at 2 hours, 44% at 4 hours, and 8% at 8 hours. A low dose (2 μg/kg) produced brain MOR blockade of 42% at 5 minutes, 6% at 2 hours, 33% at 4 hours, and 10% at 8 hours. Intranasal administration of naloxone via nasal spray has likewise been found to rapidly occupy brain MORs, with peak occupancy occurring at 20 minutes, peak occupancies of 67% at a dose of 2 mg and 85% with 4 mg, and an estimated half-life of occupancy disappearance of approximately 100 minutes (1.67 hours). Pharmacokinetics
When administered parenterally (non-orally or non-rectally, e.g., intravenously or by injection), as is most common, naloxone has a rapid distribution throughout the body.
While the onset of action is slightly delayed in this method of administration, the ease of use and portability are what make naloxone nasal sprays useful.Narcan Nasal Spray was approved in 2015 and was the first FDA-approved nasal spray for emergency treatment or suspected overdose. Narcan Nasal Spray is prepackaged, requires no assembly, and delivers a consistent 4 mg dose of naloxone. It was developed in a partnership between LightLake Therapeutics and the National Institute on Drug Abuse. The approval process was fast-tracked. A generic version of the nasal spray was approved in the United States in 2019, though did not come to market until 2021.In 2021, the FDA approved Kloxxado, a 8 mg dose of intranasal naloxone developed by Hikma Pharmaceuticals. Citing the frequent need for multiple 4 mg doses of Narcan to successfully reverse overdose, packs of Kloxxado Nasal Spray contain two pre-packaged nasal spray devices, each containing 8 mg of naloxone. However, a wedge device (nasal atomizer) can also be attached to a syringe that may also be used to create a mist to deliver the drug to the nasal mucosa. This is useful near facilities where many overdoses occur that already stock injectors. Storage
Naloxone should be stored at room temperature and protected from light. For the auto-injector, naloxone should be stored in the outer case provided. If the product is cloudy, discolored, or contains particulate matter, use is not recommended.