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
  • UK: POM (Prescription only)
Routes of
administration		 Oral, Intravenous
Pharmacokinetic data
Protein binding 45%
Metabolism hepatic
Biological half-life 10.8 ± 5.2 hours
Excretion renal
Identifiers
CAS Number 55096-26-9 N
Template:CAS (HCl)
ATC code N07BB05 (WHO)
PubChem CID: 5284594
IUPHAR/BPS 1628
ChemSpider 4447642 YesY
UNII TOV02TDP9I YesY
ChEMBL CHEMBL982 YesY
Chemical data
Formula C21H25NO3
Molecular mass 339.43 g/mol
  • 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 YesY
  • Key:WJBLNOPPDWQMCH-MBPVOVBZSA-N YesY
 NYesY (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[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

Opioid overdose

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.

Alcohol dependence

Placebo-controlled studies have shown that nalmefene, in combination with psychosocial management, significantly reduces alcohol consumption of alcohol dependent patients.[5] In the largest, recent studies, patients were instructed to take the drug "as needed", when they felt the urge to consume alcohol.[5]

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20–80 mg per day, orally.[6] The doses tested for treating pathological gambling were between 25–100 mg per day.[7] or[8] 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 can therefore be used to treat addictions at a lower dosage than what is used with naltrexone (typically 50 mg daily).[citation needed]

Side effects

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.[9]

Pharmacology

Pharmacodynamics

Nalmefene acts as a silent antagonist of the μ-opioid receptor and as a partial agonist of the κ-opioid receptor.[10] It also possesses affinity for the δ-opioid receptor.[11]

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.

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.

Properties

  • 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

Lundbeck received the European marketing authorisation for Selincro for reduction of alcohol consumption adult patients with alcohol dependence who have a high-ranking risk level without physical withdrawal; symptoms and who do not require immediate detoxification. 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.[3]

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]

See also

References

  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. ↑ https://clinicaltrials.gov/ct2/show/NCT00132119?term=nalmefene&rank=6
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ [1][dead link]
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
  8. ↑ 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
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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