Prolonged blockade of opioid effect with oral nalmefene

Abstract

In a placebo-controlled, double-blind study we evaluated the ability of a single 50 mg oral dose of nalmefene to block the effects of intravenous opioid challenge (2 micrograms/kg fentanyl). Fentanyl-induced respiratory depression (CO2 responsiveness), analgesia (tourniquet ischemia), and subjective effects were totally blocked for 48 hours and showed only minimal breakthrough 72 hours after nalmefene. Plasma concentration-time data for nalmefene indicate good oral bioavailability and a prolonged terminal elimination phase (mean t1/2 11.1 hours). These findings suggest that nalmefene could provide prolonged effectiveness in limiting emergence of opioid effects during addiction therapy.

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

“…The present results suggest slow dissociation of nalmefene from m-opioid receptors in vivo in man and are in line with the findings that nalmefene exhibits sustained clinical antagonistic action of opioid effects in the brain (Gal et al, 1986). The slow dissociation rate and high occupancy level at m-opioid receptors render nalmefene a useful drug in the reversal of opioid effects in various clinical settings (Kim et al, 1997;Mason et al, 1999).…”

“…Nalmefene is a more potent antagonist at d-opioid receptors (DeHaven-Hudkins et al, 1990;Emmerson et al, 1994) that have been implicated in alcohol drinking (Ciccocioppo et al, 2002;June et al, 2004), and the plasma terminal half-life of oral nalmefene (Dixon et al, 1987;Gal et al, 1986) markedly exceeds that of naltrexone (Meyer et al, 1984). Single oral nalmefene doses of 20-300 mg and repeated doses of 10-40 mg twice a day have been well tolerated (Dixon et al, 1987;Mason et al, 1994), and there have been no reports of any serious adverse drug reactions on hepatic or other body systems.…”

Beneficial Effects of Nalmefene Augmentation in Neuroleptic-Stabilized Schizophrenic Patients

“…We believe that this discordance is due to differences in the half-lives and the potencies of nalmefene and naloxone. Nalmefene has a much longer half-life and is approximately 50 times more po tent than naloxone (Gal et al 1986;Dixon et al 1982;Hahn et al 1975). In the WHO collaborative report, Pickar and colleagues speculated that their failure to extend the results of the single-dose trials might have been an artifact caused by the inability of repeated nal oxone infusions to produce prolonged opioid receptor blockade; our data would support this supposition (Pickar et al 1989).…”

Nalmefene for the treatment of alcohol dependence: a current update

“…Nalmefene has a comparable chemical structure to naltrexone (Swift, 2013) but was proposed to offer a number of potential advantages relative to naltrexone (Mason et al, 1999), including a more effective binding to central opioid receptors (Emmerson et al, 1994;Ingman et al, 2005), a higher bioavailability (Gal et al, 1986;Dixon et al, 1987) and the absence of a dose-dependent association with liver toxicity (Mason et al, 1999). There is no evidence of significant activity at any other receptor type (for review see Niciu and Arias, 2013).…”

“…Nalmefene has an oral bioavailability of about 40% (Gal et al, 1986;Dixon et al, 1987;Ingman et al, 2005;European Medicines Agency, 2013). There is no evidence for liver toxicity (Mason et al, 1999).…”