Nalmefene
Nalmefene, sold under the brand name Selincro among others, is an opioid antagonist medication used in the management of opioid overdose and alcohol dependence. It is taken by mouth. Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include a longer elimination half-life, greater oral bioavailability, and no observed dose-dependent liver toxicity. Nalmefene may precipitate acute withdrawal symptoms in people who are dependent on opioid drugs, or more rarely when used post-operatively, to counteract the effects of strong opioids used in surgery. Nalmefene  is available as a generic medication. Medical uses. Opioid overdose. Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose. Alcohol dependence. Nalmefene is used in the European Union 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. Very common. The following side effects of nalmefene are very common (≥10% incidence): Common. The following side effects of nalmefene are common (≥1% to <10% incidence): The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration. Pharmacology. Pharmacodynamics. Opioid receptor blockade. Nalmefene acts as an inverse agonist of the μ-opioid receptor (MOR) (K = 0.24 nM) and as a weak partial agonist (K = 0.083 nM; E = 20–30%) of the κ-opioid receptor (KOR), with similar binding  for these two receptors but a several-fold preference for the KOR. In another study however, nalmefene had approximately equal affinity for the MOR and 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 nalmefene activation of KOR may 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) (K = 16 nM), where it behaves as an antagonist. Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the C6 position of naltrexone with a methylene group (CH). It binds to the MOR with similar affinity relative to naltrexone, but binds "somewhat more avidly" to the KOR and DOR in comparison. Nalmefene with a single 1 mg dose by intravenous injection has been found to produce brain MOR blockade of 99% at  5 minutes, 90% at 2 hours, 33% at 4 hours, and 10% at 8 hours. A lower dose of 1 μg/kg intravenously resulted in brain MOR blockade of 52% at 5 minutes, 33% at 2 hours, 47% at 4 hours, and 26% at 8 hours. With oral administration, peak brain MOR occupancy of 87 to 100% was found after 3 hours with single or repeated dosing of nalmefene. At 26 hours (1.1 days) post-administration, brain MOR occupancy was 83 to 100%; at 50 hours (2.1 days), it was 48 to 72%; and at 74 hours (3.1 days), it  was 12 to 46%. The half-time of nalmefene occupancy of brain MORs is about 29 hours and is much longer than with naloxone. Substantial brain MOR occupancy occurs with nalmefene even when blood levels of nalmefene are very low. The prolonged brain MOR occupancy of nalmefene may be due to slow dissociation of nalmefene from MORs consequent to its high MOR affinity. Metabolism. 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. Society and culture. Nalmefene was first reported in a patent in 1974. United States. In the United States, immediate-release injectable nalmefene was approved in 1995, as an antidote for opioid overdose. It was sold under the brand name Revex. The product was discontinued by its manufacturer around 2008. A generic version was approved for medical use in the United States in February 2022. Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, is not available in  the United States. European Union. Danish pharmaceutical company Lundbeck 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 approved as a possible treatment supplied  by Britain's National Health Service (NHS) for reducing alcohol consumption in people with alcohol dependence. Research. Oral nalmefene was under development for the treatment of pathological gambling, interstitial cystitis, pruritus, rheumatoid arthritis, shock, and smoking withdrawal, but development was discontinued for all of these indications. Formulations of nalmefene for use by intramuscular injection, intravenous injection, and intranasal administration are in late-stage development for the treatment of opioid-related disorders. Nalmefene might be useful to treat cocaine addiction.