Clinical Pharmacology, Toxicity, and Abuse Potential of Opioids

Abstract

Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl‐laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH‐7921 and MT‐45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid‐mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half‐life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

“…Strikingly, 18.6% of drug overdose fatalities in the same year involved a prescription opioid ( Centers for Disease Control and Prevention, 2022 ). Oxycodone is one of the most prescribed opioids ( Wide-Ranging Online Data for Epidemiologic Research, 2021 ) and, despite similar half-lives (compared to hydrocodone, morphine) or reduced potency (compared to fentanyl, buprenorphine) compared to other prescription opioids, oxycodone ranked highly in abuse potential by patients with opioid use disorder (OUD; Zacny and Lichtor, 2008 ; Butler et al, 2010 ; Stoops et al, 2010 ; Remillard et al, 2019 ; Kibaly et al, 2021 ; Vearrier and Grundmann, 2021 ). Even the appropriate use of prescription opioids can lead to physical dependence and the escalation of drug consumption, contributing to the development of drug misuse and addiction ( Volkow et al, 2019 ).…”

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP

“…The half-life of F/FA varies greatly between compounds and across individuals. Fentanyl has a half-life of 1 – 9 hours ( 16 – 18 ), remifentanil has a half-life of 8 – 48 min ( 16 , 17 , 19 ), alfentanil has a half-life of 0.42 – 1.6 hours ( 16 , 18 ), and carfentanil has a half-life of 6 – 7 hours ( 16 , 20 ). The current antidotes to treat F/FA overdose are small molecule MOR antagonists such as naloxone and nalmefene.…”

Dissociable effects of oxycodone on behavior, calcium transient activity, and excitability of dorsolateral striatal neurons

“…Opioids, in particular oxycodone, are currently the treatment of choice for moderate to severe pain ( Kibaly et al, 2021 ). However, the increase in the number of oxycodone prescriptions has led to an opioid epidemic and a consequent increase in the number of opioid-related deaths ( Vearrier and Grundmann, 2021 ). An intimate knowledge of the mechanisms of opioid actions in the central nervous system is a prerequisite for the design of rational therapies against opioid addiction.…”