title: A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: a multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study.
abstract: BACKGROUND
  The combination of ibuprofen and paracetamol may confer analgesic benefits over monotherapy with either agent. In a previous study, an ibuprofen/paracetamol combination provided significantly better analgesic efficacy than comparable doses of ibuprofen or paracetamol alone in patients experiencing moderate to severe acute postoperative pain after extraction of impacted third molars.
  
  
  OBJECTIVE
  This study compared the efficacy and tolerability of 3 doses of a single-tablet fixed-dose combination (FDC) of ibuprofen and paracetamol (ibuprofen/paracetamol doses of 100 mg/250 mg, 200 mg/500 mg, and 400 mg/1000 mg) with comparable doses of ibuprofen (200 or 400 mg) monotherapy, paracetamol (500 or 1000 mg) monotherapy, and placebo in the 8 hours after surgical removal of 3 to 4 impacted third molars (stage 1) and with placebo over the next 72 hours (stage 2).
  
  
  METHODS
  This was a multicenter, 2-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study. Male or female outpatients were eligible for the study if they were aged >or=16 years, were referred for surgical removal of at least 3 impacted third molars (2 of which had to be mandibular impacted molars), and gave written informed consent. In stage 1, patients were randomly assigned to ibuprofen 200 mg, ibuprofen 400 mg, paracetamol 500 mg, paracetamol 1000 mg, FDC ibuprofen 100 mg/paracetamol 250 mg, FDC ibuprofen 200 mg/paracetamol 500 mg, FDC ibuprofen 400 mg/paracetamol 1000 mg, or placebo. In stage 2, patients who had been taking FDC therapy or placebo continued the same treatment, whereas those taking monotherapy received FDC therapy, incorporating the same dose of active monotherapy from stage 1. First-line rescue medication (hydrocodone 7.5 mg and paracetamol 500 mg) was available at any time after dosing; however, in stage 1, any patient who required rescue medication within 60 minutes of receipt of study medication was considered a "dropout" from therapy, and, in stage 2, patients who required >2 doses of first-line rescue medication in a 24-hour period were considered treatment failures. In stage 1, the primary efficacy end points were the sum of pain relief and pain intensity differences over an 8-hour follow-up period (SPRID8) and the pain relief and pain intensity difference scores at each time point (15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, and 480 minutes after dosing). Several secondary variables were also measured, including the patient's global assessment of the study medication. The 2-stopwatch method was used for measures of perceptible and meaningful pain relief. In stage 2, the primary efficacy end point was the number of completed 24-hour periods (as 0, 1, 2, or 3) in which the patient required no more than one dose of rescue medication and rated the treatment as "good," "very good," or "excellent." The tolerability of study medications was assessed in relation to the frequency, nature, and severity of adverse events (AEs), as well as their relationship to study medication; vital signs were also measured. AEs were assessed at 8 hours after dosing in stage 1, at 72 hours after dosing in stage 2, and at the follow-up visit (7-10 days after surgery); in addition, patients were instructed to report any AE that occurred between scheduled assessments.
  
  
  RESULTS
  Of 735 patients randomly assigned in stage 1, a total of 715 (97.3%) entered and 678 (92.2%) completed stage 2. Most patients were female (62.6% [460/735]) and white (91.3% [671/735]); the mean (SD) age was 20.3 (3.5) years and the mean weight was 69.7 (15.7) kg. The mean total impaction score was 11.1 (1.4), and the mean baseline pain score on the visual analog scale was 76.9 (12.0). Overall, 422 of 735 patients (57.4%) reported severe pain at baseline and 313 of 735 (42.6%) reported moderate pain. For the primary efficacy end point (SPRID8), FDC ibuprofen 400 mg/paracetamol 1000 mg was significantly more effective than ibuprofen 400 mg (P = 0.02) and paracetamol 1000 mg (P < 0.001) in the immediate postoperative period (stage 1), and FDC ibuprofen 200 mg/paracetamol 500 mg was significantly more effective than ibuprofen 200 mg (P < 0.001) and paracetamol 500 mg (P < 0.001). The FDC ibuprofen 200 mg/paracetamol 500 mg was also significantly more effective than paracetamol 1000 mg (P < 0.001), but failed to reach statistical significance in comparison with ibuprofen 400 mg. Continued postoperative therapy with all 3 FDCs on an as-needed basis was significantly more effective than placebo during the subsequent 72 hours (all, P < 0.001). During stage 1, rescue medication was required by 53 of 73 (72.6%), 29 of 75 (38.7%), 21 of 74 (28.4%), 56 of 76 (73.7%), and 51 of 74 (68.9%) patients in the placebo group and the ibuprofen 200-mg, ibuprofen 400-mg, paracetamol 500-mg, and paracetamol 1000-mg treatment groups, respectively. In the FDC treatment groups, the need for rescue medication included 27 of 71 (38.0%), 40 of 143 (28.0%), and 32 of 149 (21.5%) patients in the ibuprofen 100-mg/paracetamol 250-mg, ibuprofen 200-mg/paracetamol 500-mg, and ibuprofen 400-mg/paracetamol 1000-mg groups, respectively. The rates of treatment-related AEs between the first and second doses of study medication were significantly lower for FDC ibuprofen 400 mg/paracetamol 1000 mg (8/149 patients [5.4%]) than for placebo (14/73 [19.2%]; P < 0.01) and paracetamol 1000 mg (10/74 [13.5%]; P < 0.05); and also lower for FDC ibuprofen 200 mg/paracetamol 500 mg (9/143 [6.3%]) compared with ibuprofen 200 mg (12/75 [16.0%]; P < 0.05) and paracetamol 500 mg (17/76 [22.4%]; P < 0.001).
  
  
  CONCLUSIONS
  FDC ibuprofen 200 mg/paracetamol 500 mg and ibuprofen 400 mg/paracetamol 1000 mg were significantly more effective in this population than were comparable doses of ibuprofen or paracetamol alone in moderate to severe acute dental pain and were significantly more effective than placebo in providing sustained pain relief.
authors.affiliation: D.R. Mehlisch & Associates, Palm Desert, California 92211, USA. dmehlisch@aol.com
authors.forename: Donald R
authors.initials: DR
authors.lastname: Mehlisch
authors.forename: Sue
authors.initials: S
authors.lastname: Aspley
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Daniels
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Southerden
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Christensen
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D015438:Health Behavior; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D010149:Postoperative Pain / Q000188:drug therapy*; D013997:Time Factors; D014081:Tooth Extraction / Q000009:adverse effects*; D014095:Tooth, Impacted / Q000601:surgery
chemical_list: D000700:Analgesics; D004338:Drug Combinations; D000082:Acetaminophen; D007052:Ibuprofen