Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

Cipriano A ，Apseloff G ，Kapil RP ，He E ，Shet M ，Harris SC ... -  《-》

Comparison of the μ-Opioid Receptor Antagonists Methocinnamox and Naloxone to Reverse and Prevent the Ventilatory Depressant Effects of Fentanyl, Carfentanil, 3-Methylfentanyl, and Heroin in Male Rats.

The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is hypoventilation, which can be reversed by the μ-opioid receptor (MOR) antagonist naloxone; however, because of the very short duration of action of naloxone, reemergence of MOR agonist-induced hypoventilation can occur, requiring additional doses of naloxone. The MOR antagonist methocinnamox (MCAM) antagonizes hypoventilation by the nonmorphinan fentanyl and the morphinan heroin in laboratory animals with an unusually long duration of action. Whole-body plethysmography was used to compare the potency and effectiveness of MCAM and naloxone for preventing and reversing hypoventilation by fentanyl, heroin, and the ultrapotent and longer-acting fentanyl analogs carfentanil and 3-methylfentanyl in male rats breathing normal air. Sessions comprised a 45-minute habituation period followed by intravenous administration of saline or an acute dose of MOR agonist. The rank order of potency to decrease ventilation was 3-methylfentanyl > carfentanil > fentanyl > heroin. MCAM (0.0001-0.1 mg/kg) and naloxone (0.0001-0.01 mg/kg) dose dependently reversed hypoventilation by 3-methylfentanyl (0.01 mg/kg), carfentanil (0.01 mg/kg), fentanyl (0.1 mg/kg), or heroin (3.2 mg/kg). For prevention studies, MCAM, naloxone, or vehicle was administered intravenously 22, 46, or 70 hours prior to a MOR agonist. When administered 22 hours earlier, MCAM (0.1-1.0 mg/kg) but not naloxone (1.0 mg/kg) prevented hypoventilation by each MOR agonist. This study demonstrates the effectiveness of MCAM at reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs that have a long duration of action. SIGNIFICANCE STATEMENT: The number of opioid overdose deaths increased over the past decade despite the availability of antagonists that can prevent and reverse the effects of opioids. This study demonstrates the effectiveness and long duration of action of the μ-opioid receptor (MOR) antagonist methocinnamox (MCAM) for reversing and preventing hypoventilation by MOR agonists including ultrapotent fentanyl analogs. These results provide support for the notion that MCAM has the potential to positively impact the ongoing opioid crisis by reversing and preventing opioid overdose.

Hiranita T ，Ho NP ，France CP 《-》

Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Saari TI ，Strang J ，Dale O 《-》

Pharmacokinetic Properties of an FDA-approved Intranasal Nalmefene Formulation for the Treatment of Opioid Overdose.

Nalmefene is a high-affinity, long-duration opioid antagonist that was approved in 1995 as an injection for the treatment of opiate overdose, but subsequently withdrawn (2008) for reasons other than safety or effectiveness. The dramatic rise in opioid overdose deaths over the past 7-8 years catalyzed the development of an intranasal (IN) formulation of nalmefene for the emergency treatment of opioid overdose. The studies described here compare the pharmacokinetic properties and safety profiles of an IN formulation containing nalmefene (2.7 mg in 0.1 mL) to an approved 1 mg intramuscular (IM) dose. IN nalmefene produced maximum plasma concentrations that were significantly higher than observed following the IM dose (12.2 and 1.77 ng/mL, respectively). The time to reach maximum plasma concentrations was also faster following IN administration (0.25 and 0.33 hours, respectively) with significant differences in plasma concentrations manifested as early as 2.5 minutes after administration (NCT04759768). The plasma half-life of nalmefene was similar following IM and IN administration (10.6-11.4 hours). Furthermore, dose-normalized nalmefene exposure was similar for both 1 spray in each nostril and 2 sprays in the same nostril compared to a single spray in each nostril (NCT05219669). There were no sex differences in the pharmacokinetic properties of either IN or IM nalmefene. In an era when almost 90% of opioid overdose deaths have been linked to high-potency synthetic opioids, the ability to rapidly deliver high concentrations of nalmefene could represent an important tool for reducing both morbidity and mortality.

Crystal R ，Ellison M ，Purdon C ，Skolnick P ... -  《Clinical Pharmacology in Drug Development》

Take-home naloxone in multicentre emergency settings: the TIME feasibility cluster RCT.

Snooks H ，Benger J ，Bell F ，Black S ，Dixon S ，Emery H ，Evans BA ，Fuller G ，Hoskins R ，Hughes J ，Jones J ，Jones M ，Johnston S ，Long J ，Moore C ，Parab R ，Pilbery R ，Sampson FC ，Watkins A ... -  《-》