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In a placebo-controlled, double-blind study we evaluated the ability of a single 50 mg oral dose of nalmefene to block the effects of intravenous opioid challenge (2 micrograms/kg fentanyl). Fentanyl-induced respiratory depression (CO2 responsiveness), analgesia (tourniquet ischemia), and subjective effects were totally blocked for 48 hours and showed only minimal breakthrough 72 hours after nalmefene. Plasma concentration-time data for nalmefene indicate good oral bioavailability and a prolonged terminal elimination phase (mean t1/2 11.1 hours). These findings suggest that nalmefene could provide prolonged effectiveness in limiting emergence of opioid effects during addiction therapy.