Nalmefene

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Nalmefene
Nalmefene sceletal.svg
Clinical data
Trade names Selincro
AHFS/Drugs.com Monograph
MedlinePlus a605043
Routes of
administration		 Oral, Intravenous
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Protein binding 45%
Metabolism hepatic
Biological half-life 10.8 ± 5.2 hours
Excretion renal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
ECHA InfoCard 100.164.948
Chemical and physical data
Formula C21H25NO3
Molar mass 339.43 g/mol
3D model (Jmol)
 NYesY (what is this?)  (verify)

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid antagonist developed in the early 1970s,[1] used primarily in the management of alcohol dependence. It has also been investigated for the treatment of other addictions such as pathological gambling.[2]

Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity.[3] As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.

Medical uses[edit]

Opioid overdose[edit]

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opiate overdose,[4] although this is not the usual application for this drug as naloxone is less expensive.

Doses greater than 1.5 mg do not appear to give any greater benefit in this application. The half-life of nalmefene is longer than that of naloxone, which might make it useful for treating overdose involving longer acting opioids such as methadone, in that it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.

Alcohol dependence[edit]

The usefulness of nalmefene is unclear for alcoholism.[5] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drank in people who are alcohol dependent.[5][6] The medication can also be taken "as needed", when a person feels the urge to consume alcohol.[6]

Research[edit]

There is a case report of nalmefene being effective as an "as-needed" long-term therapy for cravings in a female patient with cocaine addiction.[7] Nalmefene may possess unique potential in the application of cocaine addiction relative to other opioid antagonists such as naltrexone due to its activity as a partial agonist of the κ-opioid receptor.[8][9]

Side effects[edit]

The most common side effects (seen in more than 1 patient in 10) were nausea (feeling sick), dizziness, insomnia (difficulty sleeping), and headache. The majority or these reactions were mild or moderate and of short duration.[10]

Pharmacology[edit]

Pharmacodynamics[edit]

Nalmefene acts as a silent antagonist 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 affinity for these two receptors but a several-fold preference for the KOR.[8][11][12] 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.[8][13] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.[14] It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety.[15] 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 shows agonistic activity.[8][12][16]

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.[8][13]

Pharmacokinetics[edit]

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]

Properties[edit]

  • Soluble in water up to 130 mg/mL, soluble in chloroform up to 0.13 mg/mL
  • pKa 7.6
  • Distribution half-life: 41 minutes

Approvals[edit]

United States[edit]

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.[17][18] 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.[3]

Europe[edit]

Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[19] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[20] The drug was approved for use in the EU in March 2013.[21] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[22] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[23] 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. Formal guidance on its use was issued by the National Institute for Health and Care Excellence (NICE).[24]

See also[edit]

References[edit]

  1. ^ US patent 3814768, Jack Fishman et al, "6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts", published 1971-11-26, issued 1974-06-04 
  2. ^ NCT00132119 ClinicalTrials.gov
  3. ^ a b See: "Drug Record: Nalmefene". LiverTox. National Library of Medicine. 24 March 2016. 
  4. ^ Label information. U.S. Food and Drug AdministrationArchived October 13, 2006, at the Wayback Machine.
  5. ^ 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 4687857Freely accessible. PMID 26694529. 
  6. ^ a b Paille, François; Martini, Hervé (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 4133028Freely accessible. PMID 25187751. 
  7. ^ Grosshans, Martin; Mutschler, Jochen; Kiefer, Falk (2015). "Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist". International Clinical Psychopharmacology. 30 (4): 237–238. doi:10.1097/YIC.0000000000000069. ISSN 0268-1315. PMID 25647453. 
  8. ^ a b c d e Bart, Gavin; Schluger, James H; Borg, Lisa; Ho, Ann; Bidlack, Jean M; Kreek, Mary Jeanne (2005). "Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?". Neuropsychopharmacology. 30 (12): 2254–2262. doi:10.1038/sj.npp.1300811. ISSN 0893-133X. PMID 15988468. 
  9. ^ Bidlack, Jean M (2014). "Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence". Adv. Pharmacol. 69: 387–418. doi:10.1016/B978-0-12-420118-7.00010-X. ISSN 1054-3589. PMID 24484983. 
  10. ^ "Selincro". European Medicines Agency. Retrieved 3 November 2015. 
  11. ^ Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ (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. 
  12. ^ a b 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. 
  13. ^ a b Niciu, Mark J.; Arias, Albert J. (2013). "Targeted opioid receptor antagonists in the treatment of alcohol use disorders". CNS Drugs. 27 (10): 777–787. doi:10.1007/s40263-013-0096-4. ISSN 1172-7047. PMC 4600601Freely accessible. PMID 23881605. 
  14. ^ "Nalmefene (new drug) Alcohol dependence: no advance". Prescrire International. 23 (150): 150–152. 2014. PMID 25121147.  (subscription required)
  15. ^ Stephen M. Stahl (15 May 2014). Prescriber's guide: Stahl's essential psychopharmacology. Cambridge University Press. pp. 465–. ISBN 978-1-139-95300-9. 
  16. ^ Grosshans M, Mutschler J, Kiefer F (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. 
  17. ^ See: "Baxter discontinues Revex injection". Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Retrieved 10 October 2016. 
  18. ^ "Drug Shortages". FDA Center for Drug Evaluation and Research. Archived from the original on 26 December 2008. 
  19. ^ "Efficacy of nalmefene in patients with alcohol dependence (ESENSE1)". 
  20. ^ "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". The Pharma Letter. 22 December 2011. 
  21. ^ "Selincro". European Medicines Agency. 13 March 2013. 
  22. ^ "Alcohol cravings drug nalmefene granted approval in Scotland". BBC News. 7 October 2013. 
  23. ^ "Nalmefene granted approval in England". The Independent. 3 October 2014. 
  24. ^ "Nalmefene for reducing alcohol consumption in people with alcohol dependence". NICE technology appraisal guidance [TA325]. NICE - UK Government body. November 2014. Retrieved August 15, 2015. 
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