Nalmefene is an opiate receptor antagonist which is used to treat acute opioid overdose and in the management of alcohol dependence and addictive behaviors. Nalmefene has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.
Nalmefene (nal’ me feen) is a semisynthetic opiate receptor antagonist which is similar structurally to naltrexone and oxymorphone. Nalmefene is distinctive in having antagonist activity against all three types of opiate receptors – μ, κ and δ. When given intravenously or intramuscularly, nalmefene causes rapid onset of withdrawal symptoms in opioid dependent persons and has been used successfully to treat acute opioid overdose. It is also used to reverse opioid actions in the postoperative period. It has a longer duration of action than naloxone and better oral availability. 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. Nalmefene is available in solutions for injection in concentrations of 100 μg/mL (for postoperative use) and 1 mg/mL (for management of known of suspected opioid overdose) under the trade name Revex. Side effects of parenterally administered nalmefene in opioid dependent patients include mood changes, sweating, anxiety, restlessness, trembling, dizziness, flushing, headache, nausea, vomiting, cardiac tachyarrhythmias, seizures, chest pain and acute pulmonary edema—symptoms of acute opioid withdrawal. In persons not taking opioids, nalmefene has minimal effects. Nalmefene is not a controlled substance, but its use is sometimes restricted to medical staff trained in emergency medicine or anesthesia.
Therapy with nalmefene has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. Nalmefene is extensively metabolized in the liver, but largely by glucuronidation rather than transformation to a different metabolite. Patients with opioid overdose often have underlying chronic liver diseases such as alcoholic liver disease, hepatitis B or C, but treatment with nalmefene does not appear to exacerbate those conditions.
REPRESENTATIVE TRADE NAMES
Nalmefene – Revex®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 28 January 2014
Zimmerman HJ. Narcotic analgesics. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 710-11. (Expert review of hepatotoxicity published in 1999; mentions that trials of naltrexone have reported serum aminotransferase elevations in up to 30% of recipients, an effect that appeared to be partially dose dependent; nalmefene not discussed).
Larrey D, Ripault MP. Illegal and recreational compounds. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 456-7. (Review of hepatotoxicity discusses buprenorphine, an orally available morphine analogue, which has been linked to cases of severe acute liver injury, usually as a result of intravenous administration; nalmefene not discussed).
Yaksh TL, Wallace MS. Opioids, analgesia, and pain management. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman.s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 481-525. (Textbook of pharmacology and therapeutics).
Dixon R, Gentile J, Hsu HB, Hsiao J, Howes J, Garg D, Weidler D. Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist. J Clin Pharmacol 1987; 27: 233-9. PubMed Citation (Phase 1 study of safety of single injections and 7 day courses of nalmefene in different doses found no increases in serum aminotransferase levels).
Kaplan JL, Marx JA. Effectiveness and safety of intravenous nalmefene for emergency department patients with suspected narcotic overdose: a pilot study. Ann Emerg Med 1993 Feb; 22(2): 187-90. PubMed Citation (Among 53 patients with suspected opioid overdose who were treated with 1-10 boluses of either 0.5 and 1.0 mg of intravenous nalmefene, no serious adverse events were found; side effects possibly related to nalmefene were vomiting, dizziness and diarrhea).
Mason BJ, Ritvo EC, Morgan RO, Salvato FR, Goldberg G, Welch B, Mantero-Atienza E. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994; 18: 1162-7. PubMed Citation (Controlled trial of 12 weeks of nalmefene or placebo in 21 alcohol dependent patients found no difference in laboratory measures during therapy, serum ALT levels decreasing in abstinent patients).
Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner ML, Jenkins JB, et al. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998; 27: 679-84. PubMed Citation (Open label trial of nalmefene for 2-26 months in 14 patients with liver disease and pruritus found "no consistent effect of nalmefene on the severity of cholestasis, as assessed by routine serum biochemical markers").
Kaplan JL, Marx JA, Calabro JJ, Gin-Shaw SL, Spiller JD, Spivey WL, Gaddis GM, Zhao N, Harchelroad FP Jr. Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Ann Emerg Med 1999; 34: 42-50. PubMed Citation (Controlled trial of two doses of nalmefene vs naloxone in 118 patients with suspected opioid overdose found similar rates of response and adverse events; the most common ones attributed to nalmefene were vomiting, tachycardia, nausea and myoclonus).
Anton RF, Pettinati H, Zweben A, Kranzler HR, Johnson B, Bohn MJ, McCaul ME, et al. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 2004; 24: 421-8. PubMed Citation (Among 270 recently abstinent alcohol dependent subjects treated with one of 3 doses of nalmefene or placebo for 12 weeks, side effects of nausea, dry mouth, insomnia, dizziness and confusion were more common in nalmefene treated patients; no mention of ALT and AST results).
Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none to nalmefene, naltrexone or other agents used to treated substance abuse).
van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol 2013; 48: 570-8. PubMed Citation (Retrospective analysis of 667 alcohol dependent patients treated with nalmefene or placebo on an as-needed basis for 6 months found decrease in average GGT and ALT values during the study, with greater decrease in nalmefene treated subjects).
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