Nalmefene, sold under the brand name Revex among others, is a medication that is used in the treatment of opioid overdose and alcohol dependence. Nalmefene belongs to the class of opioid antagonists and can be taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

, administered by injection, or delivered through nasal administration. In terms of its

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

and

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

, nalmefene is similar to another opioid antagonist called naltrexone, as they are both derivatives of opiates. However, nalmefene offers certain advantages over naltrexone. These include a longer

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

, which means it stays in the body for a longer duration, improved absorption when taken by mouth, and no observed liver toxicity that is dependent on the dosage. Nalmefene is available as a generic medication.

Medical uses

Opioid overdose

Intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

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 Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

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): * Insomnia * Dizziness * Headache * Nausea

Common

The following side effects of nalmefene are common (≥1% to <10% incidence): * Decreased appetite * Sleep disorder * Confusional state * Restlessness * Libido decreased (including loss of libido) * Somnolence * Tremor * Disturbance in attention * Paraesthesia * Hypoaesthesia * Tachycardia * Palpitations * Vomiting * Dry mouth * Diarrhea * Hyperhidrosis * Muscle spasms * Fatigue * Asthenia * Malaise * Feeling abnormal * Weight decreased 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 In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

of the μ-opioid receptor (MOR) ( = 0.24 nM) and as a weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

(K_i = 0.083 nM; E_max = 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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' evidence indicative of KOR activation, such as elevation of serum

prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

levels due to

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

suppression and increased

hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland ( ...

activation via enhanced adrenocorticotropic hormone and

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

secretion, has been observed in humans and animals.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s typical of KOR activation such as

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s and dissociation have also been observed with nalmefene in human studies. (subscription required) It is thought that nalmefene activation of KOR may produce

dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...

and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

. In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

(DOR) (K_i = 16 nM), where it behaves as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Nalmefene is structurally related to naltrexone and differs from it by substitution of the

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

group at the C6 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 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 Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

, 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.

Legal status

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. In May 2023, the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) approved a nalmefene hydrochloride nasal spray, under the brand name Opvee, for the emergency treatment of opioid overdose in people aged twelve years of age and older. In August 2024, the FDA approved a nalmefene hydrochloride auto-injector (Zurnai) for the emergency treatment of known or suspected opioid overdose in people aged twelve years of age and older. The FDA granted the application for the nalmefene hydrochloride auto-injector fast track and priority review designations. The FDA granted approval of Zurnai to Purdue Pharma L.P. As of 2012, nalmefene in

pill Pill or The Pill may refer to: Drugs * Pill (pharmacy), referring to anything small for a specific dose of medicine * "The Pill", a general nickname for the combined oral contraceptive pill Film and television * ''The Pill'' (film), a 2011 fil ...

form, used for the treatment of 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 medication named Selincro to the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

. The medication was authorized 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 medication 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 The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...

(NHS) for reducing alcohol consumption in people with alcohol dependence.

Research

Oral nalmefene was under development for the treatment of pathological gambling,

interstitial cystitis Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the Urinary bladder, bladder and pelvic floor of unknown cause. Symptoms include urinary urgency, feeling the need to urinate right away, urinary frequency, ...

, pruritus,

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

, shock, and smoking withdrawal, but development was discontinued for all of these indications. Formulations of nalmefene for use by

intramuscular injection Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be ...

, 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.

References

{{Authority control Alkene derivatives 4,5-Epoxymorphinans Delta-opioid receptor antagonists Dissociative drugs Kappa-opioid receptor agonists Mu-opioid receptor antagonists Hydroxyarenes Tertiary alcohols Withdrawn drugs