Pharmacokinetics, bioavailability, & bioequivalence Original research| Volume 33, ISSUE 6, P728-737, June 2011

Pharmacokinetics of Extended-Release Versus Conventional Tramadol/Acetaminophen Fixed-Dose Combination Tablets: An Open-Label, 2-Treatment, Multiple-Dose, Randomized-Sequence Crossover Study in Healthy Korean Male Volunteers



      A fixed-dose combination tablet of tramadol/acetaminophen exhibits both rapid and sustained analgesic effects due to different pharmacologic activities. To prolong analgesia and improve patient convenience, an extended-release (ER) tablet of this agent has been developed.


      The aim of this study was to explore the pharmacokinetic profiles of the new ER tramadol/acetaminophen fixed-dose combination and compare them with those of a conventional immediate-release (IR) formulation after multiple dosing as a Phase I clinical exploratory trial.


      An open-label, randomized, 2-sequence crossover study was conducted in healthy volunteers. All subjects received both formulations for 4 days: either 1 IR tablet (tramadol 37.5 mg/acetaminophen 325 mg) q6h followed by 1 ER tablet (tramadol 75 mg/acetaminophen 650 mg) q12h, or vice versa. A 5-day washout period separated the 2 treatments. Tramadol and acetaminophen concentrations in plasma were determined simultaneously using LC-MS/MS, and the pharmacokinetic properties were analyzed by noncompartmental method. To compare the systemic exposure of the 2 formulations, the geometric mean ratios (GMRs) for AUC0–12,ss and the 90% CIs were calculated. Adverse events (AEs) were identified through subject interviews, recording of vital signs, physical examinations, 12-lead electrocardiography, and clinical laboratory assessments.


      Twelve healthy, nonsmoking, Korean male subjects completed the study. The mean (SD) age was 24.4 (5.2) years and the mean body weight was 65.1 (6.0) kg. The Tmax,ss for tramadol was delayed until 3 hours after the ER treatment, compared with 1 hour after the IR treatment, whereas the Tmax,ss of acetaminophen was 30 minutes after each treatment. The mean (SD) of AUC0–12,ss in the IR and ER formulations was 2789.0 (507.7) and 2638.7 (469.1) µg/h/L for tramadol and 42,635.0 (8711.2) and 40,394.3 (10,127.7) µg/h/L for acetaminophen, respectively. The GMR of ER to IR for AUC0–12,ss was 0.95 (90% CI, 0.91–0.99) for tramadol and 0.94 (90% CI, 0.89–0.99) for acetaminophen. A total of 17 AEs occurred in 9 subjects; all AEs were considered mild or moderate and resolved without medical intervention. The most frequent AEs were headache and dizziness (3 cases each).


      The ER formulation displayed a similar AUC0–12,ss to that of the IR formulation for tramadol and acetaminophen.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Reeves R.R.
        • Burke R.S.
        Tramadol: basic pharmacology and emerging concepts.
        Drugs Today (Barc). 2008; 44: 827-836
        • Scott L.J.
        • Perry C.M.
        Tramadol: a review of its use in perioperative pain.
        Drugs. 2000; 60: 139-176
        • Grond S.
        • Sablotzki A.
        Clinical pharmacology of tramadol.
        Clin Pharmacokinet. 2004; 43: 879-923
        • Grond S.
        • Meuser T.
        • Zech D.
        • et al.
        Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia.
        Pain. 1995; 62: 313-320
        • Mallet C.
        • Daulhac L.
        • Bonnefont J.
        • et al.
        Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia.
        Pain. 2008; 139: 190-200
        • Toussaint K.
        • Yang X.C.
        • Zielinski M.A.
        • et al.
        What do we (not) know about how paracetamol (acetaminophen) works?.
        J Clin Pharm Ther. 2010; 35: 617-638
        • Tallarida R.J.
        • Raffa R.B.
        Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram.
        Life Sci. 1996; 58 (PL 23–28)
        • Filitz J.
        • Ihmsen H.
        • Günther W.
        • et al.
        Supra-additive effects of tramadol and acetaminophen in a human pain model.
        Pain. 2008; 136: 262-270
        • Medve R.A.
        • Wang J.
        • Karim R.
        Tramadol and acetaminophen tablets for dental pain.
        Anesth Prog. 2001; 48: 79-81
        • Edwards J.E.
        • McQuay H.J.
        • Moore R.A.
        Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.
        J Pain Symptom Manage. 2002; 23: 121-130
        • Fricke Jr, J.R.
        • Hewitt D.J.
        • Jordan D.M.
        • et al.
        A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain.
        Pain. 2004; 109: 250-257
        • McQuay H.
        • Edwards J.
        Meta-analysis of single dose oral tramadol plus acetaminophen in acute postoperative pain.
        Eur J Anaesthesiol Suppl. 2003; 28: 19-22
        • Emkey R.
        • Rosenthal N.
        • Wu S.C.
        • et al.
        Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial.
        J Rheumatol. 2004; 31: 150-156
        • Peloso P.M.
        • Fortin L.
        • Beaulieu A.
        • et al.
        Analgesic efficacy and safeAnalgesic efficacy and safety of tramadol/acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial.
        J Rheumatol. 2004; 31: 2454-2463
        • Nachamie H.L.
        • McNicoll L.
        • Dosa D.
        Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis.
        J Am Geriatr Soc. 2005; 53 (author reply 165–166): 165
        • Bourne M.H.
        • Rosenthal N.R.
        • Xiang J.
        • et al.
        Tramadol/acetaminophen tablets in the treatment of postsurgical orthopedic pain.
        Am J Orthop (Belle Mead NJ). 2005; 34: 592-597
        • Freeman R.
        • Raskin P.
        • Hewitt D.J.
        • et al.
        • CAPSS-237 Study Group
        Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy.
        Curr Med Res Opin. 2007; 23: 147-161
      1. Ultracet® (tramadol hydrochloride/acetaminophen) Tablets.
        ([prescribing information]) Ortho-McNeil Pharmaceutical, Raritan, NJ2009
        • Bannwarth B.
        • Pehourcq F.
        • Lagrange F.
        • et al.
        Single and multiple dose pharmacokinetics of acetaminophen (paracetamol) in polymedicated very old patients with rheumatic pain.
        J Rheumatol. 2001; 28: 182-184
        • Tian Z.
        • Li D.
        • Xiaofeng G.
        • et al.
        Simultaneous determination of tramadol and acetaminophen in human plasma by LC-ESI-MS.
        Chromatographia. 2007; 66: 171-178
        • Lintz W.
        • Barth H.
        • Osterloh G.
        • Schmidt-Böthelt E.
        Bioavailability of enteral tramadol formulations.
        Arzneimittelforschung. 1986; 36: 1278-1283
        • Sarbu A.
        • Radulescu F.
        • Robertson S.
        • Bouchard S.
        Onset of analgesic effect and plasma levels of controlled-release tramadol (Tramadol Contramid once-a-day) 200-mg tablets in patients with acute low back pain.
        J Opioid Manag. 2008; 4: 285-292
        • Douglas D.R.
        • Sholar J.B.
        • Smilkstein M.J.
        A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol).
        Acad Emerg Med. 1996; 3: 740-744
        • Schug S.A.
        Combination analgesia in 2005—a rational approach: focus on paracetamol-tramadol.
        Clin Rheumatol. 2006; 25: S16-S21
        • Desmeules J.
        • Rollason V.
        • Piguet V.
        • Dayer P.
        Clinical pharmacology and rationale of analgesic combinations.
        Eur J Anaesthesiol Suppl. 2003; 28: 7-11
        • Babalola C.P.
        • Oladimeji F.A.
        • Femi-Oyewo M.N.
        Pharmacokinetics and saliva secretion of paracetamol in healthy male Nigerians.
        West Afr J Med. 2004; 23: 10-14
        • Critchley J.A.
        • Critchley L.A.
        • Anderson P.J.
        • Tomlinson B.
        Differences in the single-oral-dose pharmacokinetics and urinary excretion of paracetamol and its conjugates between Hong Kong Chinese and Caucasian subjects.
        J Clin Pharm Ther. 2005; 30: 179-184
        • McClellan K.
        • Scott L.J.
        Drugs. 2003; 63 (discussion 1087–1078): 1079-1086
        • Sanaka M.
        • Kuyama Y.
        • Mineshita S.
        • et al.
        Pharmacokinetic interaction between acetaminophen and lansoprazole.
        J Clin Gastroenterol. 1999; 29: 56-58
        • Tanner T.
        • Aspley S.
        • Munn A.
        • Thomas T.
        The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol.
        BMC Clin Pharmacol. 2010; 10: 10
        • Zapater P.
        • Lasso de la Vega M.C.
        • Horga J.F.
        • et al.
        Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status.
        Aliment Pharmacol Ther. 2004; 20: 29-36
        • Dhillon S.
        Tramadol/paracetamol fixed-dose combination: a review of its use in the management of moderate to severe pain.
        Clin Drug Investig. 2010; 30 ([published correction appears in Clin Drug Investig. 2010;30:866]): 711-738
        • Ardakani Y.H.
        • Rouini M.R.
        Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers.
        Biopharm Drug Dispos. 2007; 28: 527-534
        • Paar W.D.
        • Frankus P.
        • Dengler H.J.
        The metabolism of tramadol by human liver microsomes.
        Clin Investig. 1992; 70: 708-710
        • Eradiri O.
        • Sista S.
        • Lai J.C.
        • et al.
        Single- and multiple-dose bioequivalence of two once-daily tramadol formulations using stereospecific analysis of tramadol and its demethylated (M1 and M5) metabolites.
        Curr Med Res Opin. 2007; 23: 1593-1604
        • García Quetglas E.
        • Azanza J.R.
        • Cardenas E.
        • et al.
        Stereoselective pharmacokinetic analysis of tramadol and its main phase I metabolites in healthy subjects after intravenous and oral administration of racemic tramadol.
        Biopharm Drug Dispos. 2007; 28: 19-33