McMaster HealthTech

Author: Donna Mahboubi

Drug overdose deaths are on the rise globally. In 2019, about 600000 deaths were attributed to drug use.¹ The primary culprit: opioids, which are responsible for over 75% of drug overdose deaths.² We can reverse these overdoses with a revolutionary drug called naloxone.

Mechanism

Naloxone is an opioid antagonist, meaning it binds to opioid receptors in order to block their effects.³ It is a competitive antagonist of the Mu-type, Delta-type, and Kappa-type opioid receptors, but it has the strongest affinity toward the Mu-type receptors.⁴ This is important because Mu-type opioid receptors initiate the majority the pharmacological effects produced by opioids, such as analgesia and respiratory suppression, and also act as the primary player in the opioid-reward pathway.^5,6 Through being a competitive antagonist, naloxone competes with opioids for spots at their receptors. Naloxone has also been shown to have virtually no agonistic effects on these receptors, meaning it doesn’t induce opioid-like pharmacological effects nor physical dependance.⁴

Appropriate dosage of naloxone for various uses is very tricky as opioids are highly variable in their dosage as well as their effects on different bodies.⁷ A dose of 13 μg/kg of naloxone, which is approximately 1mg for someone who weighs 80kg, will typically occupy half of the opioid receptor sites in the human brain.⁷ However, with opioid overdoses, particularly with the rise of potent synthetic opioids such as fentanyl, this may not be enough.⁷ There are currently two FDA approved forms of naloxone delivery: injectable naloxone (intramuscular, intravenous, or subcutaneous) and naloxone nasal spray. A study done in 2019 suggests that the injectable variant produces higher levels of serum naloxone, but nasal variants, which may be more accessible for the average person, are continuously being improved.⁸ Guidelines in 2015 suggested a 0.4mg intramuscular or 2mg nasal administration for non-medical bystanders in the event of an opioid overdose.⁷ However, the FDA has recently approved a newer version of Evzio®, an intramuscular naloxone device that delivers 2mg of naloxone for bystander use.⁷

Although bystanders of opioid overdose can play a life-saving role through delivering naloxone, it is essential to get the individual professional medical care as soon as possible, especially since the antagonistic effects of naloxone are relatively short-lived compared to many common opioids such as morphine.⁷ Naloxone has no problem reaching the brain, but the issue with the duration of antagonistic effects appears to rise after the initial peak of naloxone administration.⁷ During a foundational animal study done in 1976, levels of morphine in the brains of rats remained practically constant for an hour, whereas levels of naloxone in the brain declined significantly within this time period.⁹ In summary, naloxone acts fast on the brain but doesn’t stay for long.

Importance

A study done in the USA in 2019 on 16236 drug overdose deaths shows that over 37% of these deaths occurred with a bystander present.¹⁰ Considering that over 75% of overdose deaths are caused by opioids, that’s a very large number of deaths in the USA alone which could have been prevented with proper education and access to naloxone. Furthermore, the COVID-19 pandemic has only exasperated the opioid crisis. In the USA, the 12 month frame with the greatest number of opioid overdose deaths was during the COVID-19 pandemic, with an increase of up to 98% in some jurisdictions.¹¹ In Canada, opioid overdoses deaths increased by over 50% during April to June 2020 compared to January to March 2020 or April to June 2019.¹¹ These statistics open our eyes to an increasing necessity of naloxone interventions, such as community distribution of naloxone kits. In the past two decades, community programs involving naloxone education and distribution have prevented over 10000 opioid overdoses in the USA.¹² Not only does naloxone kit distribution have the capability of saving many lives, it has also proven to be cost-effective. In a systematic review of economic analyses of the community distribution of naloxone, it was determined that community distribution was a worthwhile investment across all the populations and settings included in the review, which includes the USA, Canada, Russia, Scotland, and the UK.¹¹ In all of the nine studies included in the systematic review, except for one outlier, the incremental cost-utility ratio (ICUR) fell below the standardized willingness-to-pay (WTP) threshold of $US50,000.¹¹

Naloxone is clearly a revolutionary intervention for the global opioid crisis with scientific, social, and economic viability. There’s a lot that we still don’t know about opioids, overdoses, and interventions from a multitude of lenses. An increased focus on naloxone research, education, and distribution will only continue to increase the positive impact that naloxone has on many communities.

Works Cited:

1. UNODC. World Drug Report 2023 [Internet]. Vienna: United Nations publication; 2023 Jun p. 70. Report No.: 9789210028233. Available from: http://www.unodc.org/res/WDR-2023/WDR23_Exsum_fin_SP
2. Hedegaard H, Miniño AM, Spencer MR, Warner M. Drug Overdose Deaths in the United States, 1999–2020 [Internet]. National Center for Health Statistics; 2021 p. 8. Report No.: 428. Available from: http://www.cdc.gov/nchs/data/databriefs/db428
3. NIDA. Naloxone DrugFacts. NIH [Internet]. 2022 Jan 11; Available from: https://nida.nih.gov/publications/drugfacts/naloxone
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10. Ngai SH, Berkowitz BA, Yang JC, Hempstead J, Spector S. Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action. Anesthesiology. 1976 May 1;44(5):398–401.
11. O’Donnell J, Gladden RM, Mattson CL, Hunter CT, Davis NL. Vital Signs: Characteristics of Drug Overdose Deaths Involving Opioids and Stimulants — 24 States and the District of Columbia, January–June 2019. MMWR Morb Mortal Wkly Rep. 2020 Sep 4;69(35):1189–97.
12. Cherrier N, Kearon J, Tetreault R, Garasia S, Guindon E. Community Distribution of Naloxone: A Systematic Review of Economic Evaluations. PharmacoEconomics Open. 2022 May 1;6(3):329–42.
13. Jordan MR, Morrisonponce D. Naloxone. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Feb 5]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK441910/