This open-label, parallel study of 28 men was conducted to evaluate the pharmacokinetics and safety of fentanyl delivered by the E-TRANS (fentanyl) electrotransport transdermal system (ALZA Corporation, Palo Alto, CA). The E-TRANS (fentanyl) system provided electrically assisted, transdermal, continuous delivery of fentanyl. Treatments consisted of no current (group A); a constant current of 100 µA for 26 hours plus 4 additional doses at varying currents for varying times during hour 25 (groups B, C, D); a constant current of 100 µA for 26 hours plus 4 additional doses at 1,200 µA over 2.5 minutes during hour 1 (group E); or 500 µA for 0.5 hours and 100 µA for 3.5 hours (group F). No fentanyl was detected in serum when no current had been applied. Mean serum fentanyl concentrations were similar regardless of current duration during hour 25 (treatments B, C, D). Increases in mean serum fentanyl concentrations were significantly lower during additional dosing for treatment E compared with treatments B, C, and D. Serum fentanyl concentrations sufficient for analgesia (1-3 ng/mL) were attained in treatments using the E-TRANS (fentanyl) system with basal current of 100 µA for 26 hours. There were no safety issues after treatment with E-TRANS (fentanyl) system with concurrent opioid antagonist (naltrexone) administration. The only adverse event requiring treatment was a headache (n = 1). The majority of subjects had no or barely perceptible erythema at the application site 24 hours after system removal. Application of E-TRANS (fentanyl) resulted in therapeutically significant serum fentanyl concentrations over a range of applied currents. Overall serum fentanyl concentrations were higher when the skin had been primed by constant-current fentanyl delivery.