title: A 2-week, multicenter, randomized, double-blind, double-dummy, add-on study of the effects of titration on tolerability of tramadol/acetaminophen combination tablet in Korean adults with knee osteoarthritis pain.
abstract: BACKGROUND
  Combined tramadol/acetaminophen is used to treat pain related to osteoarthritis. However, adverse events (AEs) leading to discontinuation can occur. Dose titration may decrease the risk for AEs.
  
  
  OBJECTIVE
  The aim of this study was to assess the effect of tramadol/acetaminophen titration on the development of AEs leading to treatment discontinuation in patients with knee osteoarthritis.
  
  
  METHODS
  This 2-week, multicenter, randomized, double-blind, double-dummy, add-on study was conducted at 12 tertiary referral university hospitals in the Republic of Korea. Patients aged 35 to 75 years with knee osteoarthritis receiving a stable dose of NSAIDs and with a daily mean pain-intensity score of > or = 4 on a numeric rating scale (NRS) (0 = no pain to 10 = worst pain) during the 48 hours prior to enrollment were eligible. Patients were randomly assigned to receive 1 tablet of tramadol/acetaminophen 37.5/325 mg QD and 1 placebo BID for 3 days, followed by 1 active tablet BID and 1 placebo QD for 4 days, followed by 1 active tablet TID for 7 days (titration group) or 1 tablet of combined tramadol 37.5 mg/acetaminophen 325 mg TID for 14 days (nontitration group). The primary outcome measure was the rate of treatment discontinuation due to AEs. Secondary outcome measures were time to discontinuation due to AEs, prevalences and characteristics of AEs, decrease from baseline in pain intensity as measured on the NRS, and change in the Korean version of the Western Ontario and McMaster Universities (K-WOMAC) index score (scale: 0 = best to 100 = worst).
  
  
  RESULTS
  A total of 250 patients were enrolled (92.0% female; mean [SD] age, 60.2 [7.8] years; mean [SD] weight, 60.0 [9.2] kg [range, 37.5-90.7 kg]; all Korean). The discontinuation rate was significantly lower in the titration group than in the nontitration group (10.5% vs 26.2%; P < 0.001). The Kaplan-Meier survival curve showed that the rates of discontinuation due to AEs were similar in the 2 groups up to day 2, but thereafter the discontinuation rate was significantly lower in the titration group. The most common AEs were nausea (12.1% and 24.6% in the titration and nontitration groups, respectively; P = 0.008), vomiting (4.0% and 17.2%; P < 0.001), and dizziness (9.7% and 22.1%; P = 0.005). No serious AEs were reported in either group. Tramadol/acetaminophen use was associated with a similar decrease from baseline in pain in both the titration and nontitration groups (mean [SD] Delta: NRS, -1.60 [1.62] vs -1.68 [1.58]; total K-WOMAC, -12.86 [13.73] vs -12.52 [16.58]).
  
  
  CONCLUSIONS
  In this population of Korean patients with knee osteoarthritis pain managed with a stable dose of NSAIDs, titration of tramadol/acetaminophen over 12 days was associated with improved tolerability and a significantly lower discontinuation rate compared with nontitration. Both regimens significantly reduced from baseline associated with osteoarthritis.
authors.affiliation: Department of Internal Medicine, The Hospital for Rheumatic Diseases, Hanyang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chan-Bum
authors.initials: CB
authors.lastname: Choi
authors.forename: Jung Soo
authors.initials: JS
authors.lastname: Song
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
authors.forename: Chang Hee
authors.initials: CH
authors.lastname: Suh
authors.forename: Jisoo
authors.initials: J
authors.lastname: Lee
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Choe
authors.forename: Choong Ki
authors.initials: CK
authors.lastname: Lee
authors.forename: Seung Cheol
authors.initials: SC
authors.lastname: Shim
authors.forename: Won Tae
authors.initials: WT
authors.lastname: Chung
authors.forename: Gwan Gyu
authors.initials: GG
authors.lastname: Song
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Kim
authors.forename: Jong Dae
authors.initials: JD
authors.lastname: Ji
authors.forename: Eon Jeong
authors.initials: EJ
authors.lastname: Nam
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Hong
authors.forename: Dong Hyuk
authors.initials: DH
authors.lastname: Sheen
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Lim
authors.forename: Young Ii
authors.initials: YI
authors.lastname: Seo
authors.forename: Yoon-Kyoung
authors.initials: YK
authors.lastname: Sung
authors.forename: Tae-Hwan
authors.initials: TH
authors.lastname: Kim
authors.forename: Jong-Tae
authors.initials: JT
authors.lastname: Lee
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy*; D010352:Patient Dropouts; D014147:Tramadol / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*