Nalmefene

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Nalmefene
Nalmefene sceletal.svg
Systematic (IUPAC) name
17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
Clinical data
Trade names Selincro
AHFS/Drugs.com monograph
MedlinePlus a605043
Legal status
Routes Oral, Intravenous
Pharmacokinetic data
Protein binding 45%
Metabolism hepatic
Half-life 10.8 ± 5.2 hours
Excretion renal
Identifiers
CAS number 55096-26-9 N
58895-64-0 (HCl)
ATC code N07BB05
PubChem CID 5284594
ChemSpider 4447642 YesY
UNII TOV02TDP9I YesY
ChEMBL CHEMBL982 YesY
Chemical data
Formula C21H25NO3 
Mol. mass 375.9 g/mol (hydrochloride)
 N (what is this?)  (verify)

Nalmefene (trade name Selincro), originally known as nalmetrene, is an opioid receptor 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 and addiction to shopping.[medical citation needed]

Structure and mechanism of action[edit]

Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity.[2] 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.

Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH2), which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors. It is a partial agonist of the κ-opioid receptor.[3]

Treatment of opiod overdose[edit]

Intravenous doses of nalmefene at between 0.5 to 1 milligram 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 of nalmefene greater than 1.5 mg do not appear to give any greater benefit in this application. Nalmefene's longer half-life might however make it useful for treating overdose involving longer acting opioids such as methadone, as it would require less frequent dosing and hence reduce the likelihood of renarcotization as the antagonist wears off.

Treatment of alcohol dependence[edit]

Placebo-controlled studies have shown that nalmefene, in combination with psychosocial management, significantly reduces alcohol consumption of alcohol dependent patients.[3] In the largest, recent studies, patients were instructed to take the drug "as needed", when they felt the urge to consume alcohol.[3]

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.[5] The doses tested for treating pathological gambling were between 25–100 mg per day.[6] or [7] In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20 and 25 mg, respectively) was the best tolerated, with similar therapeutic efficacy to the higher doses and less side effects. Nalmefene is thus around twice as potent as naltrexone when used for the treatment of addictions.

The use of nalmefene to reduce alcohol drinking was discovered by David Sinclair. Research with his team at the Finnish National Institute for Health and Welfare showed that it worked through the mechanism of pharmacological extinction. Each time alcohol is consumed while an opioid antagonist blocks reinforcement, the subsequent craving is incrementally reduced; alcohol drinking decreases progressively, week after week, following an extinction curve.[8][9][10] This is also known as The Sinclair Method (TSM). The theory and science supporting the TSM protocol with both nalmefene and naltrexone are described in the book The Cure for Alcoholism.

Metabolism[edit]

Nalmefene is extensively metabolised 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.

Side effects[edit]

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]

Nalmefene was approved for use in the United States in 1995 as a therapy of opioid overdose. Oral formulations, which have been used to treat alcohol dependence and other addictive behaviors, have not been approved for this use in the United States.[2]

Lundbeck has licensed the drug from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[12] In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[13] The drug was approved for use in the EU in March 2013.[14] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[15] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[16]

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. ^ a b "Drug Record Nalmefene". LiverTox, National Library of Medicine. 
  3. ^ a b c François Paille and Hervé Martini (2014). "Nalmefene: a new approach to the treatment of alcohol dependence". Substance Abuse and Rehabilitation (5): 87–94. 
  4. ^ [1][dead link]
  5. ^ Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). "A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence". Arch Gen Psychiatry 56 (8): 719. doi:10.1001/archpsyc.56.8.719. 
  6. ^ Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
  7. ^ http://journals.psychiatryonline.org/article.aspx?articleid=178053 Multicenter Investigation of the Opioid Antagonist Nalmefene in the Treatment of Pathological Gambling American Journal of Psychiatry Feb 1 2006
  8. ^ "An Error Occurred Setting Your User Cookie". Informahealthcare.com. Retrieved 22 October 2014. 
  9. ^ "Invited Review" (PDF). Hamsnetwork.org. Retrieved 22 October 2014. 
  10. ^ "United States Patent: 5086058". Hamsnetwork.org. Retrieved 22 October 2014. 
  11. ^ Nalmefene Hydrochloride Drug Information, Professional
  12. ^ "Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)". 
  13. ^ "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". thepharmaletter. 22 December 2011. 
  14. ^ "Selincro". European Medicines Agency. 13 March 2013. 
  15. ^ "Alcohol cravings drug nalmefene granted approval in Scotland". BBC. 7 October 2013. 
  16. ^ "Nalmefene granted approval in England". The Independent. 3 October 2014.