Nalmefene

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

Nalmefene
Clinical data
Trade namesSelincro
AHFS/Drugs.comMonograph
MedlinePlusa605043
License data
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Protein binding45%
MetabolismHepatic
Elimination half-life10.8 ± 5.2 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.948
Chemical and physical data
FormulaC21H25NO3
Molar mass339.435 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

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.[2]

Like other drugs of this type, nalmefene may 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

Opioid overdose

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

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[4] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.[5]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.[6] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.[6][7] The medication may also be taken "as needed", when a person feels the urge to consume alcohol.[7]

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.[8]

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 affinity for these two receptors but a several-fold preference for the KOR.[9]

[10][11] 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.[9][12] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.[13] It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety.[14] 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.[9][11][15]

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.[9][12]

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.[16]

Society and culture

Nalmefene was first reported in a patent in 1974.[17]

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.[18][19] 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.[2]

Europe

Danish pharmaceutical company Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[20] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[21] The drug was approved for use in the EU in March 2013.[22] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[23] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[24] 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.[25]

Research

Nalmefene is a partial agonist of the κ-opioid receptor and may be useful to treat cocaine addiction.[26]

See also

References
  1. Clinical trial number NCT00132119 at ClinicalTrials.gov
  2. See: "Drug Record: Nalmefene". LiverTox. National Library of Medicine. 24 March 2016.
  3. Label information. U.S. Food and Drug Administration"Archived copy" (PDF). Archived from the original on October 13, 2006. Retrieved 2014-11-07.CS1 maint: archived copy as title (link) CS1 maint: bot: original URL status unknown (link)
  4. "Selincro 18mg film-coated tablets". UK Electronic Medicines Compendium. September 2016.
  5. "Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence". NICE. 26 November 2014.
  6. 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.
  7. 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.
  8. "Selincro". European Medicines Agency. Retrieved 3 November 2015.
  9. 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.
  10. 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. 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. 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.
  13. "Nalmefene. Alcohol dependence: no advance". Prescrire International. 23 (150): 150–2. June 2014. PMID 25121147. (subscription required)
  14. Stahl SM (15 May 2014). Prescriber's guide: Stahl's essential psychopharmacology. Cambridge University Press. pp. 465–. ISBN 978-1-139-95300-9.
  15. 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.
  16. Fulton BS (2014). Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. p. 341. ISBN 9781118889572.
  17. U.S. Patent 3,814,768
  18. See: "Baxter discontinues Revex injection". Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Retrieved 10 October 2016.
  19. "Drug Shortages". FDA Center for Drug Evaluation and Research. Archived from the original on 26 December 2008.
  20. "Efficacy of nalmefene in patients with alcohol dependence (ESENSE1)".
  21. "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". The Pharma Letter. 22 December 2011.
  22. "Selincro". European Medicines Agency. 13 March 2013.
  23. "Alcohol cravings drug nalmefene granted approval in Scotland". BBC News. 7 October 2013.
  24. "Nalmefene granted approval in England". The Independent. 3 October 2014.
  25. "Alcohol dependence treatment accepted for NHS use". MIMS. 26 November 2014.
  26. 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. 69. pp. 387–418. doi:10.1016/B978-0-12-420118-7.00010-X. ISBN 9780124201187. PMID 24484983.
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