Nalmefene

Nalmefene (Revex) is an opioid receptor antagonist used primarily in the management of alcohol dependence, and also has been investigated for the treatment of other addictions such as pathological gambling and addiction to shopping.

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. 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 (CH2) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a "universal antagonist" for its ability to block all three.

In clinical trials using this drug, doses used for treating alcoholism were in the range of 20mg - 80mg per day, orally. The doses tested for treating pathological gambling were between 25mg - 100mg per day. In both trials, there was little difference in efficacy between the lower and higher dosage regimes, and the lower dose (20mg and 25mg 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.

Intravenous doses of nalmefene at between 0.5 to 1 milligram have been shown effective at counteracting the respiratory depression produced by opiate overdose, although this is not the usual application for this drug as naloxone is less expensive.

Doses of nalmefene greater than 1.5mg 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.

Nalmefene is extensively metabolised in the liver, mainly by conjugation with glucuronide and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucoronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal activity.

Soluble in water up to 130mg/mL, soluble in chloroform up to 0.13 mg/mL

CAS number of hydrochloride salt: 58895-64-0

pKa 7.6

Distribution half-life: 41 minutes

Side effects: common: drowsiness, hypertension, tachycardia, dizziness, nausea, vomiting; occasional: fever, hypotension, vasodilatation, chills, headache; rare: agitation, arrhythmia, bradycardia, confusion, hallucinations, myoclonus, itching.