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Nalmefene

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Nalmefene
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
Protein binding45%
MetabolismLiver
Elimination half-life10.8 ± 5.2 hours
ExcretionKidney
Identifiers
  • 17-Cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.948 Edit this at Wikidata
Chemical and physical data
FormulaC21H25NO3
Molar mass339.435 g·mol−1
3D model (JSmol)
  • OC(C1=C2[C@@]34[C@H]5O1)=CC=C2C[C@@H](N(CC4)CC6CC6)[C@]3(O)CCC5=C
  • InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1 checkY
  • Key:WJBLNOPPDWQMCH-MBPVOVBZSA-N checkY
  (verify)

Nalmefene is an opioid antagonist medication used in the management of opioid overdose and alcohol dependence.[1][2] 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.[4] 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.[medical citation needed]

Nalmefene is available as a generic medication.[5]

Medical uses

Opioid overdose

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.[2]

Alcohol dependence

Nalmefene is used in the European Union to reduce alcohol dependence[1] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.[6]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.[7] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.[7][8] The medication may also be taken "as needed", when a person feels the urge to consume alcohol.[8]

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.[9]

Pharmacology

Pharmacodynamics

Opioid receptor blockade

Nalmefene at human opioid receptors
Affinities (KiTooltip Inhibitor constant) Ratios Refs
MORTooltip μ-Opioid receptor KORTooltip κ-Opioid receptor DORTooltip δ-Opioid receptor MOR:KOR:DOR
0.24 nM 0.083 nM 16 nM 3:1:193 [10][11]
0.3 nM 0.3 nM 7.3 nM 1:1:24 [12][13]

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.[10][11] In another study however, nalmefene had approximately equal affinity for the MOR and KOR.[12][13] 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.[10][14] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.[15] It is thought that nalmefene activation of KOR may produce dysphoria and anxiety.[16] 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.[10][11][17]

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.[10][14]

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.[18] 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.[18] With oral administration, peak brain MOR occupancy of 87 to 100% was found after 3 hours with single or repeated dosing of nalmefene.[19][20] 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%.[19][20] The half-time of nalmefene occupancy of brain MORs is about 29 hours and is much longer than with naloxone.[19][21] Substantial brain MOR occupancy occurs with nalmefene even when blood levels of nalmefene are very low.[19][20] The prolonged brain MOR occupancy of nalmefene may be due to slow dissociation of nalmefene from MORs consequent to its high MOR affinity.[19][20]

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.[22]

Society and culture

Nalmefene was first reported in a patent in 1974.[23]

United States

In the United States, immediate-release injectable nalmefene was approved in 1995, as an antidote for opioid overdose.[24] It was sold under the brand name Revex.[2] The product was discontinued by its manufacturer around 2008.[25][26][27] A generic version was approved for medical use in the United States in February 2022.[5][28]

Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, is not available in the United States.[4]

European Union

Danish pharmaceutical company Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[29] In 2011, they submitted an application for their drug termed Selincro to the European Medicines Agency.[30] The drug was approved for use in the EU in March 2013.[31] and in October 2013, Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[32] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[33] 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.[34]

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.[35] 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.[36][37]

Nalmefene might be useful to treat cocaine addiction.[38]

References

  1. ^ a b c "Selincro 18mg film-coated tablets". UK Electronic Medicines Compendium. September 2016.
  2. ^ a b c d "Revex- nalmefene hydrochloride injection, solution". DailyMed. Retrieved 11 February 2022.
  3. ^ "Selincro EPAR". European Medicines Agency. Retrieved 11 February 2022.
  4. ^ a b "Nalmefene". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Library of Medicine. 24 March 2020. PMID 31643618. Bookshelf ID: NBK548295.
  5. ^ a b "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 11 February 2022. Retrieved 11 February 2022.
  6. ^ "Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence". NICE. 26 November 2014.
  7. ^ a b Palpacuer C, Laviolle B, Boussageon R, Reymann JM, Bellissant E, Naudet F (December 2015). "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. doi:10.1371/journal.pmed.1001924. PMC 4687857. PMID 26694529.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ a b Paille F, Martini H (2014). "Nalmefene: a new approach to the treatment of alcohol dependence". Substance Abuse and Rehabilitation. 5 (5): 87–94. doi:10.2147/sar.s45666. PMC 4133028. PMID 25187751.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ "Selincro". European Medicines Agency. Retrieved 3 November 2015.
  10. ^ a b c d e Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ (December 2005). "Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?". Neuropsychopharmacology. 30 (12): 2254–62. doi:10.1038/sj.npp.1300811. PMID 15988468.
  11. ^ a b c 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.
  12. ^ a b Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (March 1998). "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. PMID 9686407.
  13. ^ a b Clark SD, Abi-Dargham A (October 2019). "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. doi:10.1016/j.biopsych.2019.05.012. PMID 31376930. S2CID 162168648.
  14. ^ a b Niciu MJ, Arias AJ (October 2013). "Targeted opioid receptor antagonists in the treatment of alcohol use disorders". CNS Drugs. 27 (10): 777–87. doi:10.1007/s40263-013-0096-4. PMC 4600601. PMID 23881605.
  15. ^ "Nalmefene. Alcohol dependence: no advance". Prescrire International. 23 (150): 150–2. June 2014. PMID 25121147. (subscription required)
  16. ^ Stahl SM (15 May 2014). Prescriber's guide: Stahl's essential psychopharmacology. Cambridge University Press. pp. 465–. ISBN 978-1-139-95300-9.
  17. ^ Grosshans M, Mutschler J, Kiefer F (July 2015). "Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience". International Clinical Psychopharmacology. 30 (4): 237–8. doi:10.1097/YIC.0000000000000069. PMID 25647453.
  18. ^ a b Colasanti, Alessandro; Lingford-Hughes, Anne; Nutt, David (2013). "Opioids Neuroimaging". In Miller, Peter M. (ed.). Biological Research on Addiction. Comprehensive Addictive Behaviors and Disorders. Vol. 2. Elsevier. pp. 675–687. doi:10.1016/B978-0-12-398335-0.00066-2. ISBN 9780123983350.
  19. ^ a b c d e Soyka M, Rösner S (November 2010). "Nalmefene for treatment of alcohol dependence". Expert Opin Investig Drugs. 19 (11): 1451–9. doi:10.1517/13543784.2010.522990. PMID 20868291. S2CID 9227860.
  20. ^ a b c d Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H (December 2005). "Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing". Neuropsychopharmacology. 30 (12): 2245–53. doi:10.1038/sj.npp.1300790. PMID 15956985. S2CID 2453226.
  21. ^ Kim S, Wagner HN, Villemagne VL, Kao PF, Dannals RF, Ravert HT, Joh T, Dixon RB, Civelek AC (November 1997). "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. PMID 9374341.
  22. ^ Fulton BS (2014). Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. p. 341. ISBN 9781118889572.
  23. ^ U.S. patent 3,814,768
  24. ^ https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/020459Orig1s000rev.pdf [bare URL PDF]
  25. ^ "Baxter discontinues Revex injection". Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Retrieved 10 October 2016.
  26. ^ "Drug Shortages". FDA Center for Drug Evaluation and Research. Archived from the original on 26 December 2008.
  27. ^ "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". Federal Register. 3 November 2017. Retrieved 11 February 2022.
  28. ^ "Nalmefene hydrochloride: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 11 February 2022.
  29. ^ "Efficacy of nalmefene in patients with alcohol dependence (ESENSE1)" (Document). 5 July 2013. {{cite document}}: Cite document requires |publisher= (help); Unknown parameter |url= ignored (help)
  30. ^ "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". The Pharma Letter. 22 December 2011.
  31. ^ "Selincro". European Medicines Agency. 13 March 2013.
  32. ^ "Alcohol cravings drug nalmefene granted approval in Scotland". BBC News. 7 October 2013.
  33. ^ "Nalmefene granted approval in England". The Independent. 3 October 2014. Archived from the original on 18 June 2022.
  34. ^ "Alcohol dependence treatment accepted for NHS use". MIMS. 26 November 2014.
  35. ^ "Nalmefene oral - Acorda Therapeutics/Lundbeck A/S - AdisInsight".
  36. ^ "Nalmefene hydrochloride injection - Purdue Pharma - AdisInsight".
  37. ^ "Intranasal nalmefene - Opiant Pharmaceuticals - AdisInsight".
  38. ^ Bidlack JM (2014). "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. Vol. 69. pp. 387–418. doi:10.1016/B978-0-12-420118-7.00010-X. ISBN 9780124201187. PMID 24484983.
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