Central N-methyl-d-aspartate receptors modulate postoperative pain. We compared the effects of preincision oral dextromethorphan (DM), an N-methyl-d-aspartate receptor antagonist, on postoperative IV patient-controlled analgesia morphine demand and on subjective variables in 80 patients undergoing lower-body procedures who were randomly assigned to epidural lidocaine (LA; 16 mL, 1.6%) or general anesthesia (GA). The patients were premedicated 90 min before surgery with placebo or DM 90 mg (20 patients per group) in a double-blinded manner. Postoperative IV patient-controlled analgesia morphine administration started when subjective pain intensity was ≥4 of 10 (visual analog scale) and lasted 2 h. Observation continued up to 3 days, during which patients could use diclofenac. LA-DM and GA-DM patients required 45%–50% less morphine and diclofenac compared with their placebo counterparts (P < 0.001). However, GA-DM patients made twice as many attempts to self-administer morphine as LA-DM patients (P = 0.005). Eight LA-DM versus two GA-DM patients (P < 0.01) used no morphine or diclofenac. All DM patients experienced significantly (P < 0.001) less pain, were less sedated, and felt better than their placebo counterparts; however, compared with placebo, DM improved subjective scorings in the GA patients more significantly (P < 0.05) than in the LA patients. We conclude that oral DM 90 mg in patients undergoing surgery under LA or GA reduces morphine and diclofenac use by ∼50% in the immediate and late postoperative period compared with placebo. Subjectively scored levels of pain, sedation, and well-being were better as well.