Nalmefene

Another agent of this general type is nalmefene (47) Despite their useful characteristics, opiates display tolerance, addiction, abuse, and some toxic side effects Antagonists combat some of these effects, most notably respiratory depression and addiction Nalmefene reputedly has significant oral activity as a narcotic antagonist The synthesis of nalmefine concludes by Wittig olefination of naltrexone (46) to nalmefene (47) This molecular transformation resulted in a significant increase in oral potency as well (141... 

Opioidergic agents. Naltrexone and nalmefene, opioid antagonists with no intrinsic agonist properties, have been studied for the treatment of alcohol dependence. Naltrexone has been studied much more extensively than nalmefene for this indication. In 1984 naltrexone was approved by the FDA for the treatment of opioid dependence, and in 1994 it was approved for the treatment of alcohol dependence. Nalmefene is approved in the United States as a parenteral formulation for the acute reversal of opioid effects (e.g., after opioid overdose or analgesia). 

Anton RF, Pettinati H, Zweben A, et al A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 24 421 28, 2004 Aragon CM, Stotland LM, Amit Z Studies on ethanol-brain catalase interaction evidence for central ethanol oxidation. Alcohol Clin Exp Res 15 165-169, 1991 Arizzi MN, Correa M, Betz AJ, et al Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats studies with low and high rate operant schedules. Behav Brain Res 147 203—210, 2003 Azrin NH, Sisson RW, Meyers R, et al Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psychiatry 13 105—112, 1982 Babor TF, Kranzler HR, Lauerman RL Social drinking as a health and psychosocial risk factor Anstie s limit revisited, in Recent Developments in Alcoholism, Vol 5. Edited by Galanter M. New York, Plenum, 1987, pp 373 02... 

Mason BJ, RitvoEC, Morgan RO, etal A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCL for alcohol dependence. Alcohol Clin Exp Res 18 1162-1167, 1994... 

Mason BJ, Salvato FR, Williams LD, et al A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 56 719—724,1999... 

Anton RF, Pettinati H, Zwehen A, et al A multi-site dose ranging smdy of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 24 421 28, 2004 Azrin NH Improvements in the community reinforcement approach to alcoholism. Behav Res Ther 14 339-348, 1976... 

Nabazenil, 209 Naboctate, 209 Nafimidone, 90 Naflocort, 75 Nafoxidine, 65 Naftifme, 55 Nalmefene, 62 Naltrexone, 62 Napamezole, 87 Narcotic antagonist, 62 Nedocromil, 8 Nefazodone, 98 Neflumozide, 133 Netobimin, 36 Neuromuscular blocker, 69 Nifedipine, 106 Nilvadipine, 107 Nisoxetine, 30 Nitromifene, 65 Nizatidine, 95 Nomifensine, 146... 

Administration Titrate nalmefene to reverse the undesired effects of opioids. Once adequate reversal has been established, additional administration is not required and actually may be harmful due to unwanted reversal of analgesia or precipitated withdrawal. 

Patients tolerant to or physically dependent on op/o/c/s. Nalmefene may cause acute withdrawal symptoms in individuals who have some degree of tolerance to and dependence on opioids. Closely observe these patients for symptoms of withdrawal. Administer subsequent doses with intervals of at least 2 to 5 minutes between doses to allow the full effect of each incremental dose of nalmefene to be reached. Reversal of postoperative opioid depression Use 100 mcg/mL dosage strength (blue label) refer to the following table for initial doses. The goal of treatment with nalmefene in the postoperative setting is to achieve reversal of excessive opioid effects without inducing a complete reversal and acute pain. This is best accomplished with an initial dose of 0.25 mcg/kg followed by 0.25 mcg/kg... 

Nalmefene Dosage for Reversal of Postoperative Opioid Depression ... 

Cardiovascular risk patients In cases where the patient is known to be at increased cardiovascular risk, it may be desirable to dilute nalmefene 1 1 with saline or sterile water and use smaller initial and incremental doses of 0.1 mcg/kg. 

Management of known/suspected opioid overdose Use 1 mg/mL dosage strength (green label). The recommended initial dose of nalmefene for nonopioid dependent patients is 0.5 mg/70 kg. If needed, this may be followed by a second dose of 1 mg/70 kg, 2 to 5 minutes later. If a total dose of 1.5 mg/70 kg has been administered without clinical response, additional nalmefene is unlikely to have an effect. 

Pharmacology Nalmefene, an opioid antagonist, is a 6-methylene analog of naltrexone. Nalmefene prevents or reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Nalmefene has no opioid agonist activity it does not produce respiratory depression, psychotomimetic effects or pupillary constriction, and no pharmacological activity was observed when it was administered in the absence of opioid agonists. Nalmefene can produce acute withdrawal symptoms in individuals who are opioid-dependent. 

Absorption - Nalmefene is completely bioavailable following IM or subcutaneous administration. Nalmefene will be administered primarily as an IV bolus however, it can be given IM or subcutaneous if venous access cannot be established. While the time to maximum plasma concentration was 2.3 hours following IM and 1.5 hours following subcutaneous administrations, therapeutic plasma concentrations are likely to be reached within 5 to 15 minutes after a 1 mg dose in an emergency. 

Distribution - Following a 1 mg parenteral dose, nalmefene was rapidly distributed. A 1 mg dose blocked more than 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally and at steady state are 3.9 and 8.6 L/kg, respectively. Over a concentration range of 0.1 to 2 mcg/mL, 45% is bound to plasma proteins. 

Metabolism - Nalmefene is metabolized by the liver, primarily by glucuronide conjugation, and excreted in the urine less than 5% is excreted in the urine unchanged, and 17% is excreted in the feces. 

Excretion - After IV administration of 1 mg to healthy males, plasma concentrations declined biexponentially with a redistribution and a terminal elimination half-life of 41 34 minutes and 10.8 5.2 hours, respectively. The systemic clearance of nalmefene is 0.8 L/h/kg and the renal clearance is 0.08 L/h/kg. 

Emergency use Nalmefene is not the primary treatment for ventilatory failure. In most emergency settings, treatment with nalmefene should follow, not precede, the establishment of a patent airway, ventilatory assistance, administration of oxygen, and establishment of circulatory access. 

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