nalmefene

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.

Nalmefene is used in the European Union to reduce alcohol dependence{{cite web|title=Selincro 18mg film-coated tablets|url=https://www.medicines.org.uk/emc/medicine/27609|publisher=UK Electronic Medicines Compendium|date=September 2016|access-date=13 June 2017|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427131849/https://www.medicines.org.uk/emc/medicine/27609|url-status=live}} and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.{{cite web|title=Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence|url=https://www.nice.org.uk/guidance/ta325/chapter/1-Guidance|publisher=NICE|date=26 November 2014|access-date=13 June 2017|archive-date=27 March 2021|archive-url=https://web.archive.org/web/20210327013905/https://www.nice.org.uk/guidance/ta325/chapter/1-Guidance|url-status=live}}

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.{{cite journal | vauthors = Palpacuer C, Laviolle B, Boussageon R, Reymann JM, Bellissant E, Naudet F | title = Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials | journal = PLOS Medicine | volume = 12 | issue = 12 | pages = e1001924 | date = December 2015 | pmid = 26694529 | pmc = 4687857 | doi = 10.1371/journal.pmed.1001924 | doi-access = free }} 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.{{cite journal | vauthors = Paille F, Martini H | title = Nalmefene: a new approach to the treatment of alcohol dependence | journal = Substance Abuse and Rehabilitation | volume = 5 | pages = 87–94 | year = 2014 | pmid = 25187751 | pmc = 4133028 | doi = 10.2147/sar.s45666 | number = 5 | doi-access = free }}

The following side effects of nalmefene are very common (≥10% incidence):

• Insomnia
• Dizziness
• Headache
• Nausea

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.{{cite web|title=Selincro|url=https://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124|website=European Medicines Agency|access-date=3 November 2015|archive-date=24 October 2015|archive-url=https://web.archive.org/web/20151024102617/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F002583%2Fhuman_med_001620.jsp&mid=WC0b01ac058001d124|url-status=live}}

Nalmefene acts as an inverse agonist of the μ-opioid receptor (MOR) ({{abbrlink|K_i|Inhibitor constant}} = 0.24 nM) and as a weak partial agonist (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.{{cite journal | vauthors = Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ | title = Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity? | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2254–62 | date = December 2005 | pmid = 15988468 | doi = 10.1038/sj.npp.1300811 | doi-access = free }}{{cite book|author=Linda P. Dwoskin|title=Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse|url=https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398|date=29 January 2014|publisher=Elsevier Science|isbn=978-0-12-420177-4|pages=398–|access-date=31 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110212358/https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398|url-status=live}} 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.{{cite journal | vauthors = Niciu MJ, Arias AJ | title = Targeted opioid receptor antagonists in the treatment of alcohol use disorders | journal = CNS Drugs | volume = 27 | issue = 10 | pages = 777–87 | date = October 2013 | pmid = 23881605 | pmc = 4600601 | doi = 10.1007/s40263-013-0096-4 }} Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.{{cite journal | title = Nalmefene. Alcohol dependence: no advance | journal = Prescrire International | volume = 23 | issue = 150 | pages = 150–2 | date = June 2014 | pmid = 25121147 | url = http://english.prescrire.org/en/F11B931CD8AA2ECB608882529D799668/Download.aspx | access-date = 28 April 2016 | archive-date = 28 October 2021 | archive-url = https://web.archive.org/web/20211028140613/https://english.prescrire.org/en/Login.aspx?ReturnUrl=%2Fen%2FF11B931CD8AA2ECB608882529D799668%2FDownload.aspx | url-status = live }} (subscription required) It is thought that nalmefene activation of KOR may produce dysphoria and anxiety.{{cite book |vauthors=Stahl SM |title=Prescriber's guide: Stahl's essential psychopharmacology |url=https://books.google.com/books?id=qgNeAwAAQBAJ&pg=PA465 |date=15 May 2014 |publisher=Cambridge University Press |isbn=978-1-139-95300-9 |pages=465– |access-date=31 October 2016 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110212358/https://books.google.com/books?id=qgNeAwAAQBAJ&pg=PA465 |url-status=live }} In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower affinity for the δ-opioid receptor (DOR) (K_i = 16 nM), where it behaves as an antagonist.{{cite journal | vauthors = Grosshans M, Mutschler J, Kiefer F | title = Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience | journal = International Clinical Psychopharmacology | volume = 30 | issue = 4 | pages = 237–8 | date = July 2015 | pmid = 25647453 | doi = 10.1097/YIC.0000000000000069 }}

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 (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.{{cite book | vauthors = Colasanti A, Lingford-Hughes A, Nutt D | veditors = Miller PM | title = Biological Research on Addiction | series = Comprehensive Addictive Behaviors and Disorders | volume = 2 | chapter = Opioids Neuroimaging | date = 2013 | pages = 675–687 | publisher = Elsevier | doi = 10.1016/B978-0-12-398335-0.00066-2 | isbn = 9780123983350 }} 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.{{cite journal | vauthors = Soyka M, Rösner S | title = Nalmefene for treatment of alcohol dependence | journal = Expert Opin Investig Drugs | volume = 19 | issue = 11 | pages = 1451–9 | date = November 2010 | pmid = 20868291 | doi = 10.1517/13543784.2010.522990 | s2cid = 9227860 | url = }}{{cite journal | vauthors = Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H | title = Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2245–53 | date = December 2005 | pmid = 15956985 | doi = 10.1038/sj.npp.1300790 | s2cid = 2453226 | url = | doi-access = free }} 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.{{cite journal | vauthors = Kim S, Wagner HN, Villemagne VL, Kao PF, Dannals RF, Ravert HT, Joh T, Dixon RB, Civelek AC | title = Longer occupancy of opioid receptors by nalmefene compared to naloxone as measured in vivo by a dual-detector system | journal = J Nucl Med | volume = 38 | issue = 11 | pages = 1726–31 | date = November 1997 | pmid = 9374341 | doi = | url = }} 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.

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.{{citation needed|date=April 2016}}

Nalmefene is a derivative of naltrexone and was first reported in 1975.{{cite book| vauthors = Fulton BS |title=Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies|date=2014|publisher=John Wiley & Sons|isbn=9781118889572|page=341|url=https://books.google.com/books?id=M5E_BAAAQBAJ&pg=PT341|access-date=13 June 2017|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110212359/https://books.google.com/books?id=M5E_BAAAQBAJ&pg=PT341|url-status=live}}

Nalmefene was first reported in a patent in 1974.{{US Patent|3814768}}

In the United States, immediate-release injectable nalmefene was approved in 1995, as an antidote for opioid overdose.{{cite web | title = Nalmefene label | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020459Orig1s000rev.pdf | work = U.S. Food and Drug Administration | access-date = 12 February 2022 | archive-date = 12 February 2022 | archive-url = https://web.archive.org/web/20220212034330/https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020459Orig1s000rev.pdf | url-status = dead }} It was sold under the brand name Revex. The product was discontinued by its manufacturer around 2008.{{cite web|title=Baxter discontinues Revex injection|url=http://www.empr.com/news/baxter-discontinues-revex-injection/article/122431/|website=Monthly Prescribing Reference website|publisher=Haymarket Media, Inc|access-date=10 October 2016|date=9 July 2008|archive-date=11 October 2016|archive-url=https://web.archive.org/web/20161011142357/http://www.empr.com/news/baxter-discontinues-revex-injection/article/122431/|url-status=live}}{{cite web|title=Drug Shortages|url=https://www.fda.gov/Cder/drug/shortages/default.htm|publisher=U.S. Food and Drug Administration (FDA)|archive-url=https://web.archive.org/web/20081226211459/https://www.fda.gov/Cder/drug/shortages/default.htm|archive-date=26 December 2008}}{{cite web | title=Determination That Revex (Nalmefene Hydrochloride Injection), 0.1 Milligram Base/Milliliter and 1.0 Milligram Base/Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness | website=Federal Register | date=3 November 2017 | url=https://www.federalregister.gov/documents/2017/11/03/2017-23952/determination-that-revex-nalmefene-hydrochloride-injection-01-milligram-basemilliliter-and-10 | access-date=11 February 2022 | archive-date=28 January 2022 | archive-url=https://web.archive.org/web/20220128111008/https://www.federalregister.gov/documents/2017/11/03/2017-23952/determination-that-revex-nalmefene-hydrochloride-injection-01-milligram-basemilliliter-and-10 | url-status=live }} A generic version was approved for medical use in the United States in February 2022.{{cite web | title=Nalmefene hydrochloride: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212955 | access-date=11 February 2022 | archive-date=12 February 2022 | archive-url=https://web.archive.org/web/20220212034328/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212955 | url-status=dead }}

In May 2023, the Food and Drug Administration (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.{{cite press release | title=FDA Approves First Nalmefene Hydrochloride Auto-Injector to Reverse Opioid Overdose | website=U.S. Food and Drug Administration | date=7 August 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-nalmefene-hydrochloride-auto-injector-reverse-opioid-overdose | archive-url=https://web.archive.org/web/20240808062006/https://www.fda.gov/news-events/press-announcements/fda-approves-first-nalmefene-hydrochloride-auto-injector-reverse-opioid-overdose | url-status=dead | archive-date=8 August 2024 | access-date=8 August 2024}} {{PD-notice}} 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 form, used for the treatment of alcohol dependence and other addictive behaviors, is not available in the United States.

Danish pharmaceutical company Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.{{ClinicalTrialsGov|NCT00811720|Efficacy of nalmefene in patients with alcohol dependence (ESENSE1}} In 2011, they submitted an application for their medication named Selincro to the European Medicines Agency.{{Cite news | title = Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan | url = http://www.thepharmaletter.com/file/109811/lundbeck-submits-selincro-in-eu-novo-nordisk-files-degludec-in-japan.html | publisher = The Pharma Letter | date = 22 December 2011 | access-date = 5 March 2012 | archive-date = 23 June 2012 | archive-url = https://web.archive.org/web/20120623152657/http://www.thepharmaletter.com/file/109811/lundbeck-submits-selincro-in-eu-novo-nordisk-files-degludec-in-japan.html | url-status = live }} The medication was authorized for use in the EU in March 2013.{{cite web|title=Selincro|work=European Medicines Agency|date=13 March 2013|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124|access-date=4 October 2014|archive-date=4 September 2018|archive-url=https://web.archive.org/web/20180904052618/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F002583%2Fhuman_med_001620.jsp&mid=WC0b01ac058001d124|url-status=live}} and in October 2013, Scotland became the first country in the EU to prescribe the drug for alcohol dependence.{{cite news|title=Alcohol cravings drug nalmefene granted approval in Scotland|publisher=BBC News|date=7 October 2013|url=https://www.bbc.com/news/uk-scotland-24431152|access-date=21 June 2018|archive-date=28 April 2021|archive-url=https://web.archive.org/web/20210428094536/https://www.bbc.com/news/uk-scotland-24431152|url-status=live}} England followed Scotland by offering the medication as a treatment for problem drinking in October 2014.{{cite news |title=Nalmefene granted approval in England |work=The Independent |date=3 October 2014 |url=https://www.independent.co.uk/life-style/health-and-families/heavy-drinkers-to-be-offered-lifesaving-pill-that-helps-reduce-alcohol-consumption-9771600.html |archive-url=https://ghostarchive.org/archive/20220618/https://www.independent.co.uk/life-style/health-and-families/heavy-drinkers-to-be-offered-lifesaving-pill-that-helps-reduce-alcohol-consumption-9771600.html |archive-date=18 June 2022 |url-access=subscription |url-status=live }} 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.{{cite web|title=Alcohol dependence treatment accepted for NHS use|url=http://www.mims.co.uk/alcohol-dependence-treatment-accepted-nhs-use/health-promotion/article/1324040|publisher=MIMS|date=26 November 2014|access-date=13 June 2017|archive-date=28 April 2021|archive-url=https://web.archive.org/web/20210428113156/https://www.mims.co.uk/alcohol-dependence-treatment-accepted-nhs-use/health-promotion/article/1324040|url-status=live}}

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.{{Cite web | url = https://adisinsight.springer.com/drugs/800000302 | title = Nalmefene oral - Acorda Therapeutics/Lundbeck A/S | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 1 November 2021 | archive-date = 1 November 2021 | archive-url = https://web.archive.org/web/20211101210221/https://adisinsight.springer.com/drugs/800000302 | url-status = live }} 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.{{Cite web | url = https://adisinsight.springer.com/drugs/800055058 | title = Nalmefene hydrochloride injection - Purdue Pharma | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 1 November 2021 | archive-date = 7 November 2021 | archive-url = https://web.archive.org/web/20211107022809/https://adisinsight.springer.com/drugs/800055058 | url-status = live }}{{Cite web|url=https://adisinsight.springer.com/drugs/800051316|title=Intranasal nalmefene - Opiant Pharmaceuticals|work=AdisInsight|publisher=Springer Nature Switzerland AG|access-date=1 November 2021|archive-date=2 November 2021|archive-url=https://web.archive.org/web/20211102175638/https://adisinsight.springer.com/drugs/800051316|url-status=live}}

Nalmefene might be useful to treat cocaine addiction.{{cite book | vauthors = Bidlack JM | title = Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence | chapter = Mixed Kappa/Mu Partial Opioid Agonists as Potential Treatments for Cocaine Dependence | series = Advances in Pharmacology | volume = 69 | pages = 387–418 | year = 2014 | publisher = Elsevier | pmid = 24484983 | doi = 10.1016/B978-0-12-420118-7.00010-X | isbn = 9780124201187 }}

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Category:Alkene derivatives

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