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

• Published in: Clinical therapeutics 2007-07, Vol.29 (7), p.1381-1389
• Main Authors: Choi, Chan-Bum, MD,PhD, Song, Jung Soo, MD,PhD, Kang, Young Mo, MD,PhD, Suh, Chang Hee, MD,PhD, Lee, Jisoo, MD,PhD, Choe, Jung-Yoon, MD,PhD, Lee, Choong Ki, MD,PhD, Shim, Seung Cheol, MD,PhD, Chung, Won Tae, MD,PhD, Song, Gwan Gyu, MD,PhD, Kim, Hyun Ah, MD,PhD, Ji, Jong Dae, MD,PhD, Nam, Eon Jeong, MD,PhD, Park, Sung-Hoon, MD, Hong, Young Hoon, MD,PhD, Sheen, Dong Hyuk, MD, Lim, Mi Kyoung, MD, Seo, Young II, MD,PhD, Sung, Yoon-Kyoung, MD,PhD, Kim, Tae-Hwan, MD,PhD, Lee, Jong-Tae, MSc,PhD, Bae, Sang-Cheol, MD,PhD,MPH
• Format: Article
• Language: English
• Subjects: acetaminophen; Acetaminophen - administration & dosage; Acetaminophen - adverse effects; Acetaminophen - therapeutic use; Adult; Aged; Analgesics; Analgesics - administration & dosage; Analgesics - adverse effects; Analgesics - therapeutic use; Arthritis; Biological and medical sciences; Cancer; Diseases of the osteoarticular system; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; Hospitals; Humans; Internal Medicine; Knee; Korea; Male; Medical Education; Medical schools; Medical sciences; Medicine; Middle Aged; Miscellaneous. Osteoarticular involvement in other diseases; Osteoarthritis; Osteoarthritis, Knee - drug therapy; Osteoarthritis, Knee - physiopathology; Pain; Pain - drug therapy; Patient Dropouts; Pharmacology. Drug treatments; randomized controlled trial; Rheumatic diseases; tramadol; Tramadol - administration & dosage; Tramadol - adverse effects; Tramadol - therapeutic use; University colleges
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2007.07.015

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 ≥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] Δ: NRS, -1.60 [1.62] vs