The Pharmacological War Against and With Opioids

Abstract

Before coronavirus disease 2019 (COVID-19) hit the world, a very different epidemic was already taking hundreds of thousands of lives worldwide every year. In 2019, 130 Americans died from an opioid overdose every day, mainly due to opioid-induced respiratory depression (OIRD). The only currently available medication for treating opioid overdose is the competitive, reversible opioid receptor antagonist, naloxone, which was approved by the US Food and Drug Administration (FDA) half a century ago. Although naloxone is classed as an Essential Medicine by the World Health Organization (WHO), there is growing concern about its lack of effectiveness in treating OIRD caused by novel synthetic opioids, such as fentanyl, which combine a higher potency with faster onset and longer duration of action. In this issue of Clinical Pharmacology & Therapeutics (CPT), Amur et al. describe the FDA’s experience with regulation of naloxone products and formulations and how the agency is collaborating with external stakeholders in various ways in this critical area of public health. Two research articles in this issue illustrate the use and impact of model-based approaches in clinical pharmacology opioid research: Algera et al. present a pharmacokinetic/ pharmacodynamic (PK/PD) analysis of tolerance to fentanyl-induced OIRD in chronic opioid users and opioid-naïve individuals, whereas Sjöstedt and coworkers describe the development and use of a physiologically-based pharmacokinetic (PBPK) model to predict exposure of morphine and morphine-3-glucuronide in nonalcoholic steatohepatitis (NASH). In a second contribution from the FDA with co-authors from four other US government agencies, Throckmorton et al. summarize the development of various multi-agency medical countermeasures against OIRD, which spans civilian and military applications. Indeed, there is increased awareness that novel, potent synthetic opioids could be “weaponized” and used in warfare and terrorism. The most notorious example of this is the 2002 Dubrovka Opera House hostage crisis in Moscow, during which the Russian military allegedly ended the siege by spraying an aerosolized mixture of the synthetic opioids remifentanil and carfentanil into the building, costing the lives of at least 125 hostages. As explained by Paul Janssen 35 years ago, synthesis of carfentanil is relatively straightforward, and 1 kilogram could provide 20 million fatal doses. In the current CPT issue, France et al. provide a detailed summary of an expert meeting that was convened in 2019 by the Chemical Countermeasures Research Program (CCRP) to explore emerging alternative pharmacological approaches for treating opioid overdose in the event of weaponization of synthetic opioids, including: