Discovery, development and implementation of improved options for treating opioid overdose in the synthetic opioid era

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About this Research Topic

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Background

Opioid overdose has become the leading cause of drug deaths in the United States claiming 76,924 lives over the 12-month period ending October 2022. Today, 90% of opioid overdose deaths in the US involve illicit synthetic opioids (“synthetics”), predominately fentanyl and its analogs. The Drug Enforcement Administration recently reported that 60% of counterfeit pills contain a potentially lethal dose of fentanyl. The current overdose crisis also involves other drugs (e.g., psychostimulants, xylazine) which, when used with synthetics, complicates the management of opioid overdose. Polysubstance use/overdose is a clinical reality that cannot be ignored and represents a therapeutic opportunity.

Naloxone HCl, which the US Food and Drug Administration (FDA) first approved in 1971, remains the mainstay for opioid overdose treatment. Naloxone was originally used in emergency departments but is increasingly used in community settings by first responders (e.g., police, fire departments, emergency medical services personnel) and prescribed to laypersons for out-of-hospital administration. The FDA recently approved Narcan (4 mg naloxone HCl) as the first naloxone nasal spray product for over-the-counter nonprescription use.

However, the high potency, rapid-onset of action, and variable half-lives of synthetics (especially used chronically) present new challenges to reversing an overdose compared to opium-derived alkaloids (e.g., heroin, oxycodone). Converging lines of evidence suggest higher doses of naloxone may be needed to reverse overdoses linked to synthetic opioids. Furthermore, the effects of synthetics can/may outlast the duration of effect of naloxone. The risk of inadequately reversing an overdose far exceeds the risk of precipitating withdrawal, which can be medically managed, whereas untreated or undertreated opioid overdose can be fatal or, if the victim survives, lead to enduring neurological deficits.

This article collection will underscore the urgency and importance of academic, government, and industry collaborations to discover, develop and implement improved options for treating opioid overdose in the synthetic opioid era. Topics to be addressed include molecular and cellular differences between synthetics and opium-based alkaloids, development of more effective reversal agents (e.g., small molecules, monoclonal antibodies), agent-“agnostic” respiratory stimulants, DEA perspective on new psychoactive substances and future trends, rapid point-of-care drug devices to detect overdose, co-formulations to address polydrug overdose, strategies for bridging to OUD treatment, low-cost ambulatory devices to monitor post-discharge status, education efforts to destigmatize and improve implementation of such intervention, designing clinical trials and endpoints to evaluate overdose revival, machine-learning algorithms to predict fatal overdose, and policy landscape impacting rescue medication distribution through pharmacy and community channels.

Dr. Christian Heidbreder (CH) and Dr. Phil Skolnick (PS) are full-time employees of Indivior Inc.

CH is holding shares of Indivior Inc, and is holding the following Indivior patents: Methods for treating schizophrenia (20190015415); Psychiatric treatment for patients with gene polymorphisms (20190046532); Buprenorphine dosing regimens (11000520); Buprenorphine to treat respiratory depression (EP3863712A1).

Dr. Mark Greenwald (MKG) has received consulting and speaker fees from Indivior Inc. unrelated to this project.

Dr. Bernard Le Foll (BLF) has obtained funding from Indivior for a clinical trial sponsored by Indivior. He has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and is part of a Steering Board for a clinical trial for Indivior.

Keywords: opioids, opioid use, novel, treatments

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