Pharmacologic and Clinical Considerations of Nalmefene, a Long Duration Opioid Antagonist, in Opioid Overdose

Abstract

Opioid use disorder is a well-established and growing problem in the United States. It is responsible for both psychosocial and physical damage to the affected individuals with a significant mortality rate. Given both the medical and non-medical consequences of this epidemic, it is important to understand the current treatments and approaches to opioid use disorder and acute opioid overdose. Naloxone is a competitive mu-opioid receptor antagonist that is used for the reversal of opioid intoxication. When given intravenously, naloxone has an onset of action of approximately 2 min with a duration of action of 60–90 min. Related to its empirical dosing and short duration of action, frequent monitoring of the patient is required so that the effects of opioid toxicity, namely respiratory depression, do not return to wreak havoc. Nalmefene is a pure opioid antagonist structurally similar to naltrexone that can serve as an alternative antidote for reversing respiratory depression associated with acute opioid overdose. Nalmefene is also known as 6-methylene naltrexone. Its main features of interest are its prolonged duration of action that surpasses most opioids and its ability to serve as an antidote for acute opioid overdose. This can be pivotal in reducing healthcare costs, increasing patient satisfaction, and redistributing the time that healthcare staff spend monitoring opioid overdose patients given naloxone.

Molecular Pharmacology Profiling of Phenylfentanil and Its Analogues to Understand the Putative Involvement of an Adrenergic Mechanism in Fentanyl-Induced Respiratory Depression

“…Administration of either overdose reversal agent to those with opioid agonists on board results in opioid withdrawal symptoms. 15,16 In addition, the duration of action of these opioids may exceed that of NLX due to its short half-life of approximately 1 h, which may result in renarcotization wherein an overdose patient revived from naloxone goes into an overdose state once again after the naloxone wears off due to remaining opioid agonist. 15 What is more concerning is that NLX has a relatively low potency to reverse the respiratory depression caused by fentanyls, which has been perceived as the major cause for overdose deaths.…”

“…However, despite efforts to increase the availability and awareness surrounding NLX and nalmefene, the overdose death toll induced by fentanyl and its agonist analogues is an ongoing national crisis. − Furthermore, both NLX and nalmefene have limitations. Administration of either overdose reversal agent to those with opioid agonists on board results in opioid withdrawal symptoms. , In addition, the duration of action of these opioids may exceed that of NLX due to its short half-life of approximately 1 h, which may result in renarcotization wherein an overdose patient revived from naloxone goes into an overdose state once again after the naloxone wears off due to remaining opioid agonist . What is more concerning is that NLX has a relatively low potency to reverse the respiratory depression caused by fentanyls, which has been perceived as the major cause for overdose deaths. − Nalmefene has a half-life of 11 h, much longer than naloxone, but it is not yet clear whether nalmefene will prevent renarcotization .…”