Preliminary reports have demonstrated that the application of local heat to the transdermal fentanyl patch significantly increased systemic delivery of fentanyl. The objective of this study was to further evaluate the pharmacokinetic effect of local heat administration on fentanyl drug delivery through the transdermal fentanyl patch delivery system in volunteers. In addition, the study was intended to document the effect of heat on steady-state transdermal fentanyl delivery. This was an open, 3-period, crossover study that evaluated the pharmacokinetics and safety of 25 μg/h transdermal fentanyl administered with and without local heat. During Sessions A and B, subjects received transdermal fentanyl for a 30-hour period. During Session A, heat was applied for 1 hour at the 24-hour time point during the 30-hour period. During Session B, heat was applied for the first 4 hours and then again for 1 hour at the 24-hour time point during the 30-hour period. The order of Sessions A and B was randomized, and a minimum of 2 weeks separated the sessions. Five of the 10 subjects returned to participate in Session C. During Session C, subjects received transdermal fentanyl 25 μg/h for 18 hours. Heat was applied during the first 4 hours of administration and then again for 15-minute periods at the 12- and 16-hour time points. Arterial blood samples for determination of serum fentanyl concentration were collected. Maximum concentration (C_max), time to maximum concentration (t_max), and area under the curve (AUC) were determined for each treatment period. Sedation, vital signs, oxygen saturation, and adverse events were recorded. During a period of 36 hours, there were no significant differences in C_max, AUC, or T_max between transdermal fentanyl delivery with no heat and heat. However, significant differences were seen during the first 4 hours, with C_max and AUC values almost 3 times higher for the heated administrations than for the administrations without heat. With heat, the mean C_max was 0.63 ng/mL compared with a C_max of 0.24 ng/mL without heat (P = .007). With early heat, the mean AUC was 1.22 ng/mL · h compared with 0.42 ng/mL · h without heat (P = .003). There was no statistically significant difference between the median times to achieve peak values (T_max) during the first 4 hours. The addition of heat at 24 hours resulted in rapid increases in serum fentanyl concentrations for both groups and higher serum fentanyl concentrations for the administration that did not receive heat previously. Applying heat for 15 minutes at the 12-hour and 16-hour time points produced a rapid but short duration increase in serum fentanyl concentrations. The results suggest controlled heat might be used to significantly shorten the time needed to reach clinically important fentanyl concentrations. Controlled heat might be useful to produce rapid increases in serum concentrations for the rapid treatment of breakthrough pain.