title: A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement.
abstract: OBJECTIVE
  To evaluate the relative efficacy and safety of extended-release tramadol HCl 75 mg/acetaminophen 650 mg (TA-ER) and immediate-release tramadol HCl 37.5 mg/acetaminophen 325 mg (TA-IR) for the treatment of moderate to severe acute pain following total knee replacement.
  
  
  METHODS
  This phase III, double-blind, placebo-controlled, parallel-group study randomized 320 patients with moderate to severe pain (≥4 intensity on an 11 point numeric rating scale) following total knee replacement arthroplasty to receive oral TA-ER (every 12 hours) or TA-IR (every 6 hours) over a period of 48 hours. In the primary analysis, TA-ER was evaluated for efficacy non-inferior to that of TA-IR based on the sum of pain intensity difference (SPID) at 48 hours after the first dose of study drug (SPID48). Secondary endpoints included SPID at additional time points, total pain relief at all on-therapy time points (TOTPAR), sum of SPID and TOTPAR at all on-therapy time points (SPID + TOTPAR), use of rescue medication, subjective pain assessment (PGIC, Patient Global Impression of Change), and adverse events (AEs).
  
  
  RESULTS
  Analysis of the primary efficacy endpoint (SPID48) could not establish the non-inferiority of TA-ER to TA-IR. However, a post hoc analysis with a re-defined non-inferiority margin did demonstrate the non-inferiority of TA-ER to TA-IR. No statistically significant difference in SPID at 6, 12, or 24 hours was observed between the TA-ER and TA-IR groups. Similarly, analysis of TOTPAR showed that there were no significant differences between groups at any on-therapy time point, and SPID + TOTPAR at 6 and 48 hours were similar among groups. There was no difference in the mean frequency or dosage of rescue medication required by both groups, and the majority of patients in both the TA-ER and TA-IR groups rated their pain improvement as 'much' or 'somewhat better'. The overall incidence of ≥1 AEs was similar among the TA-ER (88.8%) and TA-IR (89.5%) groups. The most commonly reported AEs by patients treated with TA-ER and TA-IR included nausea (49.7% vs 44.4%), vomiting (28.0% vs 24.2%), and decreased hemoglobin (23.6% vs 26.1%). This study is limited by the lack of placebo control, and the invalidity of the initial non-inferiority margin.
  
  
  CONCLUSIONS
  This study demonstrated that the analgesic effect of TA-ER is non-inferior to TA-IR, and supports TA-ER as an effective and safe treatment for moderate to severe acute pain post total knee replacement.
  
  
  BACKGROUND
  Clinicaltrials.gov, NCT01814878.
authors.affiliation: Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , South Korea.
authors.forename: Yong-Beom
authors.initials: YB
authors.lastname: Park
authors.forename: Chul-Won
authors.initials: CW
authors.lastname: Ha
authors.forename: Sung-Do
authors.initials: SD
authors.lastname: Cho
authors.forename: Myung-Chul
authors.initials: MC
authors.lastname: Lee
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Lee
authors.forename: Seung-Suk
authors.initials: SS
authors.lastname: Seo
authors.forename: Seung-Baik
authors.initials: SB
authors.lastname: Kang
authors.forename: Hee-Soo
authors.initials: HS
authors.lastname: Kyung
authors.forename: Choong-Hyeok
authors.initials: CH
authors.lastname: Choi
authors.forename: NaYoon
authors.initials: N
authors.lastname: Chang
authors.forename: Hyou Young Helen
authors.initials: HY
authors.lastname: Rhim
authors.forename: Seong-Il
authors.initials: SI
authors.lastname: Bin
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use*; D059787:Acute Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010147:Pain Measurement; D010149:Postoperative Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D014147:Tramadol / Q000627:therapeutic use*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D004338:Drug Combinations; C478659:Ultracet; D000082:Acetaminophen; D014147:Tramadol
keywords: Acute pain; Pain intensity; Pain relief; Post-operative pain