|Systematic (IUPAC) name|
|Biological half-life||10.8 ± 5.2 hours|
|ATC code||N07BB05 (WHO)|
|Molar mass||339.43 g/mol|
|(what is this?)|
Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid antagonist developed in the early 1970s, used primarily in the management of alcohol dependence. It has also been investigated for the treatment of other addictions such as pathological gambling.
Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.
Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opiate overdose, although this is not the usual application for this drug as naloxone is less expensive.
Doses greater than 1.5 mg do not appear to give any greater benefit in this application. The half-life of nalmefene is longer than that of naloxone, which might make it useful for treating overdose involving longer acting opioids such as methadone, in that it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.
The usefulness of nalmefene is unclear for alcoholism. Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drank in people who are alcohol dependent. The medication can also be taken "as needed", when a person fells the urge to consume alcohol.
There is a case report of nalmefene being effective as an "as-needed" long-term therapy for cravings in a female patient with cocaine addiction. Nalmefene may possess unique potential in the application of cocaine addiction relative to other opioid antagonists such as naltrexone due to its activity as a partial agonist of the κ-opioid receptor.
The most common side effects (seen in more than 1 patient in 10) were nausea (feeling sick), dizziness, insomnia (difficulty sleeping), and headache. The majority or these reactions were mild or moderate and of short duration.
Nalmefene acts as a silent antagonist of the μ-opioid receptor (MOR) (Ki = 0.24 nM) and as a weak partial agonist (Ki = 0.083 nM; Emax = 20–30%) of the κ-opioid receptor (KOR), with similar affinity for these two receptors but a several-fold preference for the KOR. In vivo evidence indicative of KOR activation, such as elevation of serum prolactin levels due to dopamine suppression and increased hypothalamic-pituitary-adrenal axis activation via enhanced adrenocorticotropic hormone and cortisol secretion, has been observed in humans and animals. Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies. It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety. In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower affinity for the δ-opioid receptor (DOR) (Ki = 16 nM), where it shows agonistic activity.
Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH2). It binds to the MOR with similar affinity relative to naltrexone, but binds "somewhat more avidly" to the KOR and DOR in comparison.
Nalmefene is extensively metabolized in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.
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- Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
- pKa 7.6
- Distribution half-life: 41 minutes
Lundbeck received the European marketing authorisation for Selincro for reduction of alcohol consumption adult patients with alcohol dependence who have a high-ranking risk level without physical withdrawal; symptoms and who do not require immediate detoxification. Nalmefene was approved for use in the United States in 1995 as a therapy of opioid overdose. Oral formulations, which have been used to treat alcohol dependence and other addictive behaviors, have not been approved for this use in the United States.
Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence. In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency. The drug was approved for use in the EU in March 2013. and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence. England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.
- US patent 3814768, Jack Fishman et al, "6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts", published 1971-11-26, issued 1974-06-04
- NCT00132119 ClinicalTrials.gov
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