Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing

  title={Prolonged Central $\mu$-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing},
  author={Kimmo Ingman and Nora Hagelberg and Sargo Aalto and Kjell N{\aa}gren and Auni Juhakoski and Sakari Karhuvaara and Antero Kallio and Vesa Oikonen and Jarmo Hietala and Harry Scheinin},
The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central μ-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and μ-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both… 
Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects
The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations, which may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.
Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors
The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking and support the as‐needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists.
Opioid Antagonism in Humans: A Primer on Optimal Dose and Timing for Central Mu-Opioid Receptor Blockade
This work provides a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data and creates models and simulations that form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists.
Pharmacologic and Clinical Considerations of Nalmefene, a Long Duration Opioid Antagonist, in Opioid Overdose
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 and can be pivotal in reducing healthcare costs, increasing patient satisfaction, and redistributing the time that healthcare staff spend monitoring opioid overdose patients given naloxone.
Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy.
A robust population PK model for nalmefene was developed and based on the concentration-occupancy model the μ-opioid receptor occupancy after a single 20 mg dose of nalmfene is predicted to be above the target therapeutic occupancy for about 24 h in about 95% of the target population.
Targeted Opioid Receptor Antagonists in the Treatment of Alcohol Use Disorders
The targeted or ‘as-needed’ approach to treatment with opioid antagonists is an efficacious harm-reduction strategy for problem drinking and alcohol dependence.
Comparing Nalmefene and Naltrexone in Alcohol Dependence: Are there any Differences? Results from an Indirect Meta-Analysis.
An indirect meta-analysis of randomized controlled studies on the treatment of alcohol dependence indicates an advantage of nalmefene over naltrexone, an effective and well-tolerated medication for the reduction of alcohol consumption.


Longer occupancy of opioid receptors by nalmefene compared to naloxone as measured in vivo by a dual-detector system.
  • S. Kim, H. Wagner, A. Civelek
  • Biology, Medicine
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine
  • 1997
This longer blockade of opioid receptors by nalmefene represents an advantage in the clinical management of postsurgical reversal of narcotic anesthesia and opioid side effects as well as the reversal of opioid overdose.
Nalmefene: Safety and Kinetics After Single and Multiple Oral Doses of a New Opioid Antagonist
Both studies indicate that orally administered nalmefene has a wide margin of safety in healthy men and exhibits a linear pharmacokinetic profile at the doses tested.
A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence.
Treatment with nalmefene was effective in preventing relapse to heavy drinking relative to placebo in alcohol-dependent outpatients and was accompanied by acceptable side effects.
Bioequivalence, dose-proportionality, and pharmacokinetics of naltrexone after oral administration.
There was excellent linearity between the administered dose and the area under the plasma concentration-time profile, as well as total urinary recovery of both drug and metabolite.
Pharmacologic profile of NPC 168 (naltrexone phenyl oxime), a novel compound with activity at opioid receptors
Using [11C]Diprenorphine to Image Opioid Receptor Occupancy by Methadone in Opioid Addiction: Clinical and Preclinical Studies
It is suggested that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [11C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioids receptor occupancy.
Naltrexone-induced nausea in patients treated for alcohol dependence: clinical predictors and evidence for opioid-mediated effects.
The hypothesis that recency and intensity of alcohol use are related to opiate antagonist-precipitated nausea is supported and long-term alcohol use may result in alterations in the endogenous opioid system.
Prolonged blockade of opioid effect with oral nalmefene
It is suggested that nalmefene could provide prolonged effectiveness in limiting emergence of opioid effects during addiction therapy and good oral bioavailability and a prolonged terminal elimination phase.
A Multi-site Dose Ranging Study of Nalmefene in the Treatment of Alcohol Dependence
This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics, and possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmfene treatment.
A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence.
Preliminary support is provided for the hypotheses that nalmefene can be safely given to alcoholics, and that naltrexone may have a role in reducing alcohol consumption and preventing relapse, particularly at the 40 mg level.