Controlled opiate challenges of naltrexone-pretreated human subjects have established that naltrexone is an effective opioid antagonist. However, these challenges have been conducted after relatively acute dosing with naltrexone, and tolerance to this antagonism after chronic treatment is possible. We therefore administered morphine challenges in a double-blind, placebo-controlled design to nine ex-addicts who had been taking naltrexone for a mean of 9.4 months. None of the ex-addicts experienced euphoria; instead, most of these blockaded ex-addicts had a dysphoric histaminelike response to the intravenous morphine. The only physiological change was a slight increase in heart rate. We conclude that tolerance does not develop to the opioid antagonist properties of naltrexone up to as long as 21 months of treatment.