Effective management of endodontic pain represents a continuing challenge. In this study, we evaluated the efficacy of flurbiprofen and a novel centrally acting analgesic, tramadol, alone and in combination, for reducing pain in endodontic emergency patients. Patients (n = 49) were administered a local anesthetic and underwent pulpectomy. They were then administered, on a double-blind basis, either: (i) placebo (one capsule to start and then every 6 h); (ii) flurbiprofen (100 mg loading dose and then 50 mg every 6 h); (iii) tramadol (100 mg loading dose and then 100 mg every 6 h); or (iv) the combination of flurbiprofen and tramadol (as above). Pulpectomy combined with placebo medication resulted in a 50% reduction in pain by 24 h (p < 0.01). Patients treated with flurbiprofen and tramadol reported less pain, compared with placebo treatment at 6 and 24 h (p < 0.01 for both). These results suggest that a nonsteroidal anti-inflammatory drug/opiate combination, together with endodontic therapy, may be useful in the management of endodontic pain.