Chemistry:Nalmefene

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Short description: Opioid antagonist
Nalmefene
Nalmefene.svg
Clinical data
Trade namesSelincro, Revex, others
Other namesNalmetrene; 6-Desoxy-6-methylenenaltrexone; CPH-101; JF-1; Lu AA36143; NIH-10365; ORF-11676
AHFS/Drugs.comMonograph
MedlinePlusa605043
License data
Routes of
administration		By mouth, intranasal, intramuscular injection, intravenous injection, subcutaneous
Drug classOpioid antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40–50% (orally)[6]
Protein binding45%
MetabolismLiver
Elimination half-life10.8 ± 5.2 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H25NO3
Molar mass339.435 g·mol−1
3D model (JSmol)
  (verify)

Nalmefene is a medication that is used in the treatment of opioid overdose and alcohol dependence.[2][3] Nalmefene belongs to the class of opioid antagonists and can be taken by mouth, administered by injection, or delivered through nasal administration.[7]

In terms of its chemical structure and biological activity, 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, 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.[8]

Nalmefene is available as a generic medication.[9]


Medical uses

Opioid overdose

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.[3]

Alcohol dependence

Nalmefene is used in the European Union to reduce alcohol dependence[2] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.[10]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.[11] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.[11][12] The medication may also be taken "as needed", when a person feels the urge to consume alcohol.[12]

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.[13]

Pharmacology

Pharmacodynamics

Opioid receptor blockade

Nalmefene at human opioid receptors
Affinities (Ki) Ratios Refs
MOR KOR DOR MOR:KOR:DOR
0.24 nM 0.083 nM 16 nM 3:1:193 [14][15]
0.3 nM 0.3 nM 7.3 nM 1:1:24 [16][17]

Nalmefene acts as an inverse agonist 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 binding for these two receptors but a several-fold preference for the KOR.[14][15] In another study however, nalmefene had approximately equal affinity for the MOR and KOR.[16][17] 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.[14][18] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.[19] It is thought that nalmefene activation of KOR may produce dysphoria and anxiety.[20] 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 behaves as an antagonist.[14][15][21]

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.[14][18]

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.[22] 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.[22] With oral administration, peak brain MOR occupancy of 87 to 100% was found after 3 hours with single or repeated dosing of nalmefene.[23][24] 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%.[23][24] The half-time of nalmefene occupancy of brain MORs is about 29 hours and is much longer than with naloxone.[23][25] Substantial brain MOR occupancy occurs with nalmefene even when blood levels of nalmefene are very low.[23][24] The prolonged brain MOR occupancy of nalmefene may be due to slow dissociation of nalmefene from MORs consequent to its high MOR affinity.[23][24]

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.[citation needed]

Chemistry

Nalmefene is a derivative of naltrexone and was first reported in 1975.[26]

Society and culture

Nalmefene was first reported in a patent in 1974.[27]

United States

In the United States, immediate-release injectable nalmefene was approved in 1995, as an antidote for opioid overdose.[28] It was sold under the brand name Revex.[3] The product was discontinued by its manufacturer around 2008.[29][30][31] A generic version was approved for medical use in the United States in February 2022.[9][32]

In May 2023, the FDA approved a nalmefene hydrochloride nasal spray, under the brand name Opvee, for the emergency treatment of opioid overdose in people twelve years of age and older.[33]

Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, is not available in the United States.[8]

European Union

Danish pharmaceutical company Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[34] In 2011, they submitted an application for their drug termed Selincro to the European Medicines Agency.[35] The drug was approved for use in the EU in March 2013.[36] and in October 2013, Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[37] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[38] 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.[39]

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.[40] 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.[41][42]

Nalmefene might be useful to treat cocaine addiction.[43]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". 21 June 2022. https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015. 
  2. ↑ 2.0 2.1 2.2 "Selincro 18mg film-coated tablets". UK Electronic Medicines Compendium. September 2016. https://www.medicines.org.uk/emc/medicine/27609. 
  3. ↑ 3.0 3.1 3.2 3.3 "Revex- nalmefene hydrochloride injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=49fd02f8-12b8-460c-ae1f-f26738d86998. 
  4. ↑ "Opvee- nalmefene hydrochloride spray". 19 June 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=999a4269-9e54-4801-b2ac-2a7276f0b94f. 
  5. ↑ "Selincro EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/selincro. 
  6. ↑ "Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ-opioid receptor occupancy". British Journal of Clinical Pharmacology (Wiley) 81 (2): 290–300. February 2016. doi:10.1111/bcp.12805. PMID 26483076. 
  7. ↑ "FDA Approves Prescription Nasal Spray to Reverse Opioid Overdose". U.S. Food and Drug Administration (FDA) (Press release). 23 May 2023. Retrieved 1 June 2023.
  8. ↑ 8.0 8.1 "Nalmefene". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Library of Medicine. 24 March 2020. Bookshelf ID: NBK548295. https://www.ncbi.nlm.nih.gov/books/NBK548295/. Retrieved 12 February 2022. 
  9. ↑ 9.0 9.1 "Competitive Generic Therapy Approvals". 11 February 2022. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  10. ↑ "Technology appraisal guidance [TA325: Nalmefene for reducing alcohol consumption in people with alcohol dependence"]. NICE. 26 November 2014. https://www.nice.org.uk/guidance/ta325/chapter/1-Guidance. 
  11. ↑ 11.0 11.1 "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". PLOS Medicine 12 (12): e1001924. December 2015. doi:10.1371/journal.pmed.1001924. PMID 26694529. 
  12. ↑ 12.0 12.1 "Nalmefene: a new approach to the treatment of alcohol dependence". Substance Abuse and Rehabilitation 5 (5): 87–94. 2014. doi:10.2147/sar.s45666. PMID 25187751. 
  13. ↑ "Selincro". https://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 "Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?". Neuropsychopharmacology 30 (12): 2254–62. December 2005. doi:10.1038/sj.npp.1300811. PMID 15988468. 
  15. ↑ 15.0 15.1 15.2 Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–. ISBN 978-0-12-420177-4. https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398. Retrieved 31 October 2016. 
  16. ↑ 16.0 16.1 "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Res Monogr 178: 440–66. March 1998. PMID 9686407. 
  17. ↑ 17.0 17.1 "The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence". Biol Psychiatry 86 (7): 502–511. October 2019. doi:10.1016/j.biopsych.2019.05.012. PMID 31376930. 
  18. ↑ 18.0 18.1 "Targeted opioid receptor antagonists in the treatment of alcohol use disorders". CNS Drugs 27 (10): 777–87. October 2013. doi:10.1007/s40263-013-0096-4. PMID 23881605. 
  19. ↑ "Nalmefene. Alcohol dependence: no advance". Prescrire International 23 (150): 150–2. June 2014. PMID 25121147. http://english.prescrire.org/en/F11B931CD8AA2ECB608882529D799668/Download.aspx. Retrieved 28 April 2016.  (subscription required)
  20. ↑ Prescriber's guide: Stahl's essential psychopharmacology. Cambridge University Press. 15 May 2014. pp. 465–. ISBN 978-1-139-95300-9. https://books.google.com/books?id=qgNeAwAAQBAJ&pg=PA465. Retrieved 31 October 2016. 
  21. ↑ "Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience". International Clinical Psychopharmacology 30 (4): 237–8. July 2015. doi:10.1097/YIC.0000000000000069. PMID 25647453. 
  22. ↑ 22.0 22.1 "Opioids Neuroimaging". Biological Research on Addiction. Comprehensive Addictive Behaviors and Disorders. 2. Elsevier. 2013. pp. 675–687. doi:10.1016/B978-0-12-398335-0.00066-2. ISBN 9780123983350. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 "Nalmefene for treatment of alcohol dependence". Expert Opin Investig Drugs 19 (11): 1451–9. November 2010. doi:10.1517/13543784.2010.522990. PMID 20868291. 
  24. ↑ 24.0 24.1 24.2 24.3 "Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing". Neuropsychopharmacology 30 (12): 2245–53. December 2005. doi:10.1038/sj.npp.1300790. PMID 15956985. 
  25. ↑ "Longer occupancy of opioid receptors by nalmefene compared to naloxone as measured in vivo by a dual-detector system". J Nucl Med 38 (11): 1726–31. November 1997. PMID 9374341. 
  26. ↑ Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. 2014. p. 341. ISBN 9781118889572. https://books.google.com/books?id=M5E_BAAAQBAJ&pg=PT341. Retrieved 13 June 2017. 
  27. ↑ U.S. Patent 3,814,768
  28. ↑ "Nalmefene label". U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020459Orig1s000rev.pdf. 
  29. ↑ "Baxter discontinues Revex injection". Haymarket Media, Inc. 9 July 2008. http://www.empr.com/news/baxter-discontinues-revex-injection/article/122431/. 
  30. ↑ "Drug Shortages". U.S. Food and Drug Administration (FDA). https://www.fda.gov/Cder/drug/shortages/default.htm. 
  31. ↑ "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". 3 November 2017. https://www.federalregister.gov/documents/2017/11/03/2017-23952/determination-that-revex-nalmefene-hydrochloride-injection-01-milligram-basemilliliter-and-10. 
  32. ↑ "Nalmefene hydrochloride: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212955. 
  33. ↑ "FDA Approves Prescription Nasal Spray to Reverse Opioid Overdose". U.S. Food and Drug Administration (FDA) (Press release). 23 May 2023. Retrieved 1 June 2023.
  34. ↑ Clinical trial number NCT00811720 for "Efficacy of nalmefene in patients with alcohol dependence (ESENSE1" at ClinicalTrials.gov
  35. ↑ "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". The Pharma Letter. 22 December 2011. http://www.thepharmaletter.com/file/109811/lundbeck-submits-selincro-in-eu-novo-nordisk-files-degludec-in-japan.html. 
  36. ↑ "Selincro". European Medicines Agency. 13 March 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124. 
  37. ↑ "Alcohol cravings drug nalmefene granted approval in Scotland". BBC News. 7 October 2013. https://www.bbc.com/news/uk-scotland-24431152. 
  38. ↑ "Nalmefene granted approval in England". The Independent. 3 October 2014. https://www.independent.co.uk/life-style/health-and-families/heavy-drinkers-to-be-offered-lifesaving-pill-that-helps-reduce-alcohol-consumption-9771600.html. 
  39. ↑ "Alcohol dependence treatment accepted for NHS use". MIMS. 26 November 2014. http://www.mims.co.uk/alcohol-dependence-treatment-accepted-nhs-use/health-promotion/article/1324040. 
  40. ↑ "Nalmefene oral - Acorda Therapeutics/Lundbeck A/S". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800000302. 
  41. ↑ "Nalmefene hydrochloride injection - Purdue Pharma". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800055058. 
  42. ↑ "Intranasal nalmefene - Opiant Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800051316. 
  43. ↑ "Mixed Kappa/Mu Partial Opioid Agonists as Potential Treatments for Cocaine Dependence". Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence. Advances in Pharmacology. 69. Elsevier. 2014. pp. 387–418. doi:10.1016/B978-0-12-420118-7.00010-X. ISBN 9780124201187. 



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