In a clinical model of dental pain, the analgesic efficacy of local morphine treatment was examined under three different conditions. Patients undergoing dental surgery were randomly assigned to an injection of local anesthetic (articaine) plus 1 mg morphine either into inflamed (n = 14; trial 1) or non-inflamed (n = 24; trial 2) submucous tissue or perineurally n = 19; trial 3). Patients in the control group for each condition (n = 13, trial 1; n = 26, trial 2; n = 16, trial 3) received articaine plus saline. Postoperative pain intensity was assessed by the visual analog scale (VAS) and numeric rating scale (NRS) at 0, 2, 4, 6, 8, 10, 12, 16, 20, and 24 h. In addition, patients recorded the occurrence of side effects and the supplemental consumption of diclofenac. Immediately after the operation, pain scores were reduced to a similar extent in all groups, most likely due to the local anesthetic effect. Thereafter, pain scores and supplemental consumption of diclofenac were significantly lower in patients receiving 1 mg morphine into inflamed submucous tissue than in the control group for up to 24 h. Patients receiving 1 mg morphine into non-inflamed tissue or perineurally did not show any further reduction in pain scores compared to each control group. Our results show in patients undergoing dental surgery that injection of 1 mg of morphine into inflamed tissue results in significant and prolonged postoperative analgesia, whereas administration into non-inflamed tissue or perineurally is not effective. Thus, consistent with experimental studies, the requirement of an inflammatory process for the occurrence of peripheral opioid effects is also found in the clinical setting.