Nalmefene is an opioid antagonist 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 antagonistnaltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability, and no observed dose-dependent liver toxicity. Like other drugs of this type, nalmefene may 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.
Medical uses
Opioid overdose
doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose. When nalmefene is used to treat an opioid overdose, doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit than doses of only 1.5 mg.
Alcohol dependence
Nalmefene is used in Europe to reduce alcohol dependence and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily. Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear. Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent. The medication may also be taken "as needed", when a person feels the urge to consume alcohol.
Side effects
The following adverse effects have been reported with nalmefene:
The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.
Pharmacology
Pharmacodynamics
Nalmefene acts as an inverse agonist of the μ-opioid receptor and as a weak partial agonist of the κ-opioid receptor, 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 , where it behaves as an antagonist. 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. It binds to the MOR with similar affinity relative to naltrexone, but binds "somewhat more avidly" to the KOR and DOR in comparison.
Pharmacokinetics
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.
Chemistry
Nalmefene is a derivative of naltrexone and was first reported in 1975.
In the US, immediate-release injectable nalmefene was approved in 1995 as an antidote for opioid overdose. It was sold under the trade name Revex. The product was discontinued by its manufacturer around 2008. Perhaps, due to its price, it never sold well. Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, has never been sold in the United States.
Europe
has licensed nalmefene 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. In November 2014 nalmefene was appraised and approved as a treatment supplied by Britain's National Health Service for reducing alcohol consumption in people with alcohol dependence.
Research
Nalmefene is a partial agonist of the κ-opioid receptor and may be useful to treat cocaine addiction.
