Abstract
The purpose of this study is to compare the efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) with that of nonsteroidal anti-inflammatory drugs (NSAIDs) as maintenance therapy following tramadol/APAP and NSAID combination therapy in knee osteoarthritis (OA) pain which was inadequately controlled by NSAIDs. Subjects with knee OA for over 1 year and moderate pain (numerical rating scale [NRS] ≥5) despite at least 4 weeks’ NSAID therapy (meloxicam 7.5 mg or 15 mg qd or aceclofenac 100 mg bid) received tramadol/APAP add-on (combination with NSAID) for 4 weeks. Thereafter, subjects with significant pain improvement (NRS <4) were randomized to receive either tramadol/APAP or NSAID for 8 weeks. On days 29 and 57, Western Ontario and McMaster Universities (WOMAC) OA index score was measured. Secondary measures included pain intensity (NRS), pain relief score, and subjects’ and investigators’ overall medication assessments. Of 143 subjects enrolled, 112 completed the 4-week tramadol/APAP and NSAID combination phase and 97 (67.8%) experienced significant pain improvement. Of the 97 subjects randomized, 36 in tramadol/APAP group and 47 in NSAID group completed the 8-week comparator study. On days 29 and 57, WOMAC scores and pain intensities did not increase in both groups compared to measurements immediately after the combination therapy. At these two time points, there were no significant differences in WOMAC scores, pain intensities, and other secondary measures between the two groups. Overall adverse event rates were similar in both groups. Tramadol/APAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs. In those subjects who showed favorable response to tramadol/APAP and NSAID combination therapy, both tramadol/APAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadol/APAP and NSAIDs.
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References
Creamer P, Hochberg MC (1997) Osteoarthritis. Lancet 350:503–508
Felson DT, Zhang Y (1998) An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 41:1343–1355
Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA et al (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 58:26–35
Davis MA, Ettinger WH, Neuhaus JM, Mallon KP (1991) Knee osteoarthritis and physical functioning: evidence from the NHANES I Epidemiologic Followup Study. J Rheumatol 18:591–598
American College of Rheumatology Subcommittee on Osteoarthritis Guidelines (2000) Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 43:1905–1915
Jordan K, Arden N, Doherty M, Bannworth B, Bijlsma JW, Dieppe P et al (2003) EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis. Ann Rheum Dis 62:1145–1155
Zhang W, Jones A, Doherty M (2004) Does paracetamol (acetaminophen) reduce the pain of osteoarthritis?: a meta-analysis of randomized controlled trials. Ann Rheum Dis 63:901–907
Roth SH (1998) Efficacy and safety of tramadol HCL in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol 25:1358–1363
Medve RA, Wang J, Karim R (2001) Tramadol and acetaminophen tablets for dental pain. AnesthProg 48:79–81
Fricke JR Jr, Hewitt DJ, Jordan DM, Fisher A, Rosenthal NR (2004) A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. Pain 109:250–257
Peloso PM, Fortin L, Beaulieu A, Kamin M, Rosenthal N, Protocol TRP-CAN-1 Study Group (2004) Analgesic 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 31:2454–2456
Silberstein SD, Freitag FG, Rozen TD, Kudrow DB, Hewitt DJ, Jordan DM et al (2005) Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache 45:1317–1327
Bennett RM, Schein J, Kosinski MR, Hewitt DM, Jordan DM, Rosenthal NR (2005) Impact of fibromyalgia pain on health-related quality of life before and after treatment with tramadol/acetaminophen. Arthritis Rheum 53:519–527
Emkey R, Rosenthal N, Wu SC, Jordan D, Kamin M, CAPSS-114 Study Group (2004) Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal anti-inflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. J Rheumatol 31:150–156
Rosenthal NR, Silverfield JC, Wu SC, Jordan D, Kamin M, CAPSS-105 Study Group (2004) Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient population. J Am GeriatrSoc 52:374–380
Choi CB, Song JS, Kang YM, Suh CH, Lee J, Choe JY et al (2007) 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. ClinTher 29:1381–1389
Silberfield JC, Kamin M, Wu SC, Rosenthal N, CAPSS-105 Study Group (2002) Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis flare pain: a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. ClinTher 24:282–297
Katz WA (2002) Use of nonopioid analgesics and adjunctive agents in the management of pain in rheumatic diseases. Curr Opin Rheumatol 14:63–71
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K et al (1986) Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 29:1039–1049
Bae SC, Lee HS, Yun HR, Kim TH, Yoo DH, Kim SY (2001) Cross–cultural adaptation and validation of Korean Western Ontario and McMaster Universities (WOMAC) and Lequesne osteoarthritis indices for clinical research. Osteoarthr Cartil 9:746–750
Hathway GJ, Vega-Avelaira D, Moss A, Ingram R, Fitzgerald M (2009) Brief, low frequency stimulation of rat peripheral C-fibres evokes prolonged microglial-induced central sensitization in adults but not in neonates. Pain 144:110–118
Gwilym SE, Keltner JR, Warnaby CE, Carr AJ, Chizh B, Chessell I et al (2009) Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum 61:1226–1234
Neogi T, Niu J, Arendt-Nielsen L, Scholz J, Frey-Law L, Woolf C et al (2010) Central sensitization and knee pain in osteoarthritis: preliminary results from the MOST study. Arthritis Rheum 62(suppl 10):2098
Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K (2006) Mu opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology 51:651–658
Barann M, Urban B, Stamer U, Dorner Z, Bonisch H, Bruss M (2006) Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis. Eur J Pharmacol 531:54–58
Halfpenny DM, Callado LF, Hopwood SE, Bamigbade TA, Langford RM, Stamford JA (1999) Effects of tramadol stereroisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry. Br J Anaesth 83:909–915
Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P et al (2003) Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 48:1420–1429
Meeus M, Nijs J (2007) Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome. ClinRheumatol 26:465–473
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This study was supported by a grant from Janssen Korea, Ltd, Seoul, Korea.
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Park, KS., Choi, JJ., Kim, WU. et al. The efficacy of tramadol/acetaminophen combination tablets (Ultracet®) as add-on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID). Clin Rheumatol 31, 317–323 (2012). https://doi.org/10.1007/s10067-011-1818-y
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DOI: https://doi.org/10.1007/s10067-011-1818-y