Prolonged Antagonism of Opioid Action with Intravenous Nalmefene in Man

Gal, Thomas J.; DiFazio, Cosmo A.

doi:10.1097/00000542-198602000-00008

Cited by 120 publications

(26 citation statements)

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“…Our observation that the duration of nalmefene bioacti vity on the hypothalamic-pituitary axis exceeded that of na loxone is in agreement with a recent report indicating that nalmefene could block analgesia and respiratory depression produced by administration of fentanyl to human subjects 8 h after nalmefene pretreatment [8]. The extended duration of bioactivity that we and others find is probably due in part to the slower clearance rate of nalmefene.…”

Section: Discussionsupporting

confidence: 93%

Comparison of the Duration of Action of Nalmefene and Naloxone on the Hypothalamic-Pituitary Axis of the Rhesus Monkey

VanVugt

Webb²,

Reid³

1989

Neuroendocrinology

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The duration of action of nalmefene, a relatively new opiate antagonist, on the hypothalamic-pituitary axis of the rhesus monkey was compared to that exhibited by naloxone. Ovariectomized monkeys (n = 5) were pretreated with 10 mg nalmefene, 10 mg naloxone or an equivalent volume of saline 12, 24, or 48 h prior to the administration of 10 mg morphine. Blood samples were collected by venipuncture 0, 1,2,3 and 4 h after injection of morphine and were assayed for luteinizing hormone (LH) and prolactin (PRL). Duration of action of these two opiate antagonists was estimated from their ability to block morphine inhibition and stimulation of LH and PRL release respectively. Morphine reduced serum LH concentration by 60% and increased PRL levels approximately 4-fold in saline-pretreated animals. Administration of nalmefene either 12 or 24 h, but not 48 h prior to morphine, significantly antagonized the effects of this opiate on LH and PRL release. In contrast, naloxone at all pretreatment intervals failed to block morphine’s effect. We conclude that a single 10 mg bolus injection of nalmefene exerts significant activity at the opiate receptors that mediate the effects of morphine on LH and PRL release for at least 24 h after administration, whereas the same dose of naloxone has a duration of action less than 12 h. Based on this finding it is likely that the effects of endogenous opioid peptides in the rhesus monkey can be chronically antagonized by the daily administration of nalmefene.

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Section: Discussionsupporting

confidence: 93%

Comparison of the Duration of Action of Nalmefene and Naloxone on the Hypothalamic-Pituitary Axis of the Rhesus Monkey

VanVugt

Webb²,

Reid³

1989

Neuroendocrinology

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“…morphine-and bombesin-induced scratching responses. Initial experiments were conducted to compare the effect of nalmefene, a long-acting opioid antagonist (Gal and DiFazio, 1986), on the dose-response curves of i.c. morphine and bombesin on scratching.…”

Section: Experimental Designmentioning

confidence: 99%

Characterization of scratching responses in rats following centrally administered morphine or bombesin

Lee

Naughton

Woods

et al. 2003

Behavioural Pharmacology

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The aim of this study was to characterize scratching behavior elicited by central administration of morphine or bombesin in rats, and to determine the role of opioid receptors in scratching induced by both pruritogenic agents. Central administration included intracisternal (i.c.), intrathecal (i.t.), and intracerebroventricular (i.c.v.) routes. Scratching events made with hind paws were counted by observers blinded to treatment conditions. Intracisternal morphine (0.01-0.1 μg) produced dosedependent increases in scratching; the maximum response to i.c. morphine 0.1 μg was approximately 500 scratches within a 1-hour period. Neither i.t. nor i.c.v. morphine significantly increased scratching. Bombesin (0.01 -0.32 μg) elicited robust scratching following i.c. administration. The maximum response to i.c. bombesin 0.32 μg was approximately 4000 scratches within a 1-hour period. Both i.t. and i.c.v. bombesin produced profound scratching at similar doses. Antagonist studies confirmed that mu-opioid receptors selectively mediate i.c. morphine-induced scratching. However, selective mu-, kappa-, and delta-opioid antagonists did not attenuate i.c. bombesin-induced scratching. These results demonstrate that morphine and bombesin elicit scratching through different receptor mechanisms, at different central sites, and to different degrees.

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“…4) In addition to the reversal of opioid agonist effects, nalmefene provides an alternative to methadone for the treatment of opioid dependence. 1,4,5) Nalmefene has specific pharmacological properties which may make it more useful than other opioid antagonists as an abstinence treatment for opioid dependence. 4,6) The number of narcotics-abusers in China is quite staggering.…”

mentioning

confidence: 99%

“…1,4,5) Nalmefene has specific pharmacological properties which may make it more useful than other opioid antagonists as an abstinence treatment for opioid dependence. 4,6) The number of narcotics-abusers in China is quite staggering. According to statistics of government, heroin-abusers are estimated to be 0.791 million.…”

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confidence: 99%

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Optimization of the Preparation of Nalmefene-Loaded Sustained-Release Microspheres Using Central Composite Design

Yong-liang

2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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Nalmefene is a m selective opioid antagonist which is similar to naloxone in structure and pharmacology. Receptor binding studies have shown that nalmefene, like naloxone and the other opioid antagonist naltrexone, had high affinity for m, k and d receptors, furthermore, it bound more tightly with these receptors than naltrexone. [1][2][3] In animal models, nalmefene has many properties of opioid antagonist which have been demonstrated under a wide range of conditions. Studies on humans have also demonstrated opioid antagonist effects of nalmefene. 4) In addition to the reversal of opioid agonist effects, nalmefene provides an alternative to methadone for the treatment of opioid dependence. 1,4,5) Nalmefene has specific pharmacological properties which may make it more useful than other opioid antagonists as an abstinence treatment for opioid dependence. 4,6) The number of narcotics-abusers in China is quite staggering. According to statistics of government, heroin-abusers are estimated to be 0.791 million. Many relevant medical agencies had made continuous efforts to reduce the population of narcoticabusers, but seldom achieved the ideal goal. Statistics showed that 98.2% subjects who entered those treatment programs had a dismal record of relapse, and only a small proportion remained clean long after the program. The disease caused by narcotics abuse remains a scourge of society. It becomes an increasingly important task for us to help addicted individuals to get rid of their dependency or at least decrease the level of dependency to make them be a functional member of society.The relapse of addiction is often caused by the compliance and lack of retention. 5,7-9) A repetitive treatment act, such as asking subjects to take a pill daily, is not easy thing, even they have no doubt of taking the pill. When the narcoticsabuser has physiological and emotional needs for the abused substance, the therapeutic routine becomes more difficult. The lack of perseverance of the subject decreases the chance of success of the treatment. Therefore, it is of great importance to be able to reduce the level of involvement of the subject during medicinal treatments, particularly those treatments involving a particular regimen.Many experts adopt sustained-release method to reduce the involvement of compliance. Various slow-release biodegradable microspheres have been developed for a variety of drugs, and some of them are commercialized. Among various biodegradable polymers, the poly(lactic-co-glycolic acid) (PLGA) is the most widely studied and used.10-12) The properties of the microspheres are sensitive to many variableness of preparation and condition of the preparing and selecting process. In this study, we have studied the effect of formulation variables of sustained release microspheres on several response variables, and subsequently, we have utilized response surface methodology to optimize the formulation after constructing a desirable function that combines three response variables. ExperimentalMaterials and Apparatus PLGA ...

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Prolonged Antagonism of Opioid Action with Intravenous Nalmefene in Man

Cited by 120 publications

References 0 publications

Comparison of the Duration of Action of Nalmefene and Naloxone on the Hypothalamic-Pituitary Axis of the Rhesus Monkey

Comparison of the Duration of Action of Nalmefene and Naloxone on the Hypothalamic-Pituitary Axis of the Rhesus Monkey

Characterization of scratching responses in rats following centrally administered morphine or bombesin

Optimization of the Preparation of Nalmefene-Loaded Sustained-Release Microspheres Using Central Composite Design

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