Nalmefene

Nalmefene
Names
Pronunciationnal’ me feen
Trade namesSelincro, Revex, others
Other namesNalmetrene
IUPAC name
  • 17-Cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
Clinical data
Drug classOpioid antagonist.[1]
Main usesOpioid overdose, alcohol dependence[1][2]
Side effectsNausea, fast heart rate, high blood pressure[1]
Routes of
use		By mouth, intravenous
External links
AHFS/Drugs.comMonograph
US NLMNalmefene
MedlinePlusa605043
Legal
License data
Legal status
  • UK: POM (Prescription only)
Pharmacokinetics
Protein binding45%
MetabolismLiver
Elimination half-life10.8 ± 5.2 hours
ExcretionKidney
Chemical and physical data
FormulaC21H25NO3
Molar mass339.435 g·mol−1
3D model (JSmol)
SMILES
  • OC(C1=C2[C@@]34[C@H]5O1)=CC=C2C[C@@H](N(CC4)CC6CC6)[C@]3(O)CCC5=C
InChI
  • 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

Nalmefene, sold under the brand name Selincro among others, is a medication used to treat opioid overdose and alcohol dependence.[1][2] Other uses may include pathological gambling.[3] It is taken by mouth or by injection.[1][2]

Common side effects include nausea, fast heart rate, and high blood pressure.[1] Other side effects may include arrhythmias, seizures, and opioid withdrawal.[1] While there is no evidence of harm in pregnancy, such use has not been well studied.[4] It is an opioid antagonist.[1]

Nalmefene was approved for medical use in the United States in 1995.[1] In the United Kingdom 4 weeks at a dose of 18 mg per day costs the NHS about £85.[2] It was discontinued commercially in the United States in 2008.[5]

Medical uses

Opioid overdose

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.[6]

When nalmefene is used to treat an opioid overdose, doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit than doses of only 1.5 mg.

Alcohol dependence

Nalmefene is used in Europe to reduce alcohol dependence[7] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.[8]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.[9] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.[9][10] The medication may also be taken "as needed", when a person feels the urge to consume alcohol.[10]

Side effects

The following adverse effects have been reported with nalmefene:

Very common (≥1/10)

  • Insomnia
  • Dizziness
  • Headache
  • Nausea

Common (≥1/100 to <1/10)

  • 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
  • Diarrhoea
  • 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.[11]

Pharmacology

Pharmacodynamics

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.[12][13][14] 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.[12][15] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.[16] It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety.[17] 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.[12][14][18]

Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the 6-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.[12][15]

Pharmacokinetics

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.[19]

Society and culture

Nalmefene was first reported in a patent in 1974.[20]

United States

In the US, immediate-release injectable nalmefene was approved in 1995 as an antidote for opioid overdose. It was sold under the trade name "Revex". The product was discontinued by its manufacturer around 2008.[5][21] Perhaps, due to its price, it never sold well. (See § Opioid overdose, above.)

Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, has never been sold in the United States.[22]

Europe

Danish pharmaceutical company Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[23] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[24] The drug was approved for use in the EU in March 2013.[25] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[26] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[27] In November 2014 nalmefene was appraised and approved as a treatment supplied by Britain's National Health Service (NHS) for reducing alcohol consumption in people with alcohol dependence.[28]

Research

Nalmefene is a partial agonist of the κ-opioid receptor and may be useful to treat cocaine addiction.[29]

References

  1. 1 2 3 4 5 6 7 8 9 "Nalmefene Monograph for Professionals". Drugs.com. Archived from the original on 8 August 2021. Retrieved 11 November 2021.
  2. 1 2 3 4 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 518. ISBN 978-0857114105.
  3. ↑ "Nalmefene". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 13 November 2021. Retrieved 11 November 2021.
  4. ↑ "Nalmefene (Revex) Use During Pregnancy". Drugs.com. Archived from the original on 8 August 2021. Retrieved 11 November 2021.
  5. 1 2 "Baxter discontinues Revex injection". Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Archived from the original on 11 October 2016. Retrieved 10 October 2016.
  6. ↑ Label information. U.S. Food and Drug Administration"Archived copy" (PDF). Archived from the original on October 13, 2006. Retrieved 2014-11-07.{{cite web}}: CS1 maint: archived copy as title (link) CS1 maint: bot: original URL status unknown (link)
  7. ↑ "Selincro 18mg film-coated tablets". UK Electronic Medicines Compendium. September 2016. Archived from the original on 2021-04-27. Retrieved 2021-10-24.
  8. ↑ "Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence". NICE. 26 November 2014. Archived from the original on 27 March 2021. Retrieved 24 October 2021.
  9. 1 2 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.
  10. 1 2 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.
  11. ↑ "Selincro". European Medicines Agency. Archived from the original on 24 October 2015. Retrieved 3 November 2015.
  12. 1 2 3 4 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.
  13. ↑ 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.
  14. 1 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. Archived from the original on 27 April 2021. Retrieved 24 October 2021.
  15. 1 2 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.
  16. ↑ "Nalmefene. Alcohol dependence: no advance". Prescrire International. 23 (150): 150–2. June 2014. PMID 25121147. Archived from the original on 2021-10-28. Retrieved 2021-10-24. (subscription required)
  17. ↑ Stahl SM (15 May 2014). Prescriber's guide: Stahl's essential psychopharmacology. Cambridge University Press. pp. 465–. ISBN 978-1-139-95300-9. Archived from the original on 28 April 2021. Retrieved 24 October 2021.
  18. ↑ 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.
  19. ↑ Fulton BS (2014). Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. p. 341. ISBN 9781118889572. Archived from the original on 2021-04-27. Retrieved 2021-10-24.
  20. ↑ U.S. Patent 3,814,768
  21. ↑ "Drug Shortages". FDA Center for Drug Evaluation and Research. Archived from the original on 26 December 2008.
  22. ↑ See: Drug Record: Nalmefene. LiverTox. National Library of Medicine. 24 March 2016. Archived from the original on 9 April 2019. Retrieved 24 October 2021.
  23. ↑ "Efficacy of nalmefene in patients with alcohol dependence (ESENSE1)". 5 July 2013. Archived from the original on 10 May 2013. Retrieved 24 October 2021. {{cite journal}}: Cite journal requires |journal= (help)
  24. ↑ "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". The Pharma Letter. 22 December 2011. Archived from the original on 23 June 2012. Retrieved 24 October 2021.
  25. ↑ "Selincro". European Medicines Agency. 13 March 2013. Archived from the original on 4 September 2018. Retrieved 14 March 2022.
  26. ↑ "Alcohol cravings drug nalmefene granted approval in Scotland". BBC News. 7 October 2013. Archived from the original on 28 April 2021. Retrieved 24 October 2021.
  27. ↑ "Nalmefene granted approval in England". The Independent. 3 October 2014. Archived from the original on 25 September 2015. Retrieved 24 October 2021.
  28. ↑ "Alcohol dependence treatment accepted for NHS use". MIMS. 26 November 2014. Archived from the original on 28 April 2021. Retrieved 24 October 2021.
  29. ↑ 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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