Skip to main content
SpringerLink
Log in

Tramadol/Paracetamol Fixed-Dose Combination

A Review of its Use in the Management of Moderate to Severe Pain

  • Adis Drug Evaluation
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Tramadol/paracetamol 37.5mg/325mg (Tramacet®, Zaldiar®, Ixprim®, Kolibri®) is an orally administered fixed-dose combination of the atypical opioid tramadol and paracetamol, which is indicated in the EU for the symptomatic treatment of moderate to severe pain. This article reviews the pharmacological properties, clinical efficacy and tolerability of tramadol/paracetamol in adults with moderate to severe pain.

Fixed-dose tramadol/paracetamol is a rapidly-acting, longer-duration, multi-modal analgesic, which is effective and generally well tolerated in patients with moderate to severe pain. In several well designed, clinical studies, single- or multiple-dose tramadol/paracetamol was effective in providing pain relief in adult patients with postoperative pain after minor surgery, musculoskeletal pain (acute, subacute or chronic), painful diabetic peripheral neuropathy or migraine pain. It was also effective as an add-on analgesic in patients who were experiencing moderate to severe musculoskeletal pain (e.g. osteoarthritis or rheumatoid arthritis pain) despite ongoing NSAID and/or disease-modifying antirheumatic drug therapy. Moreover, in patients with postoperative pain, ankle sprain pain or subacute lower back pain, the analgesic efficacy of tramadol/paracetamol was better than that of paracetamol, generally similar to, or better than that, of tramadol, and generally similar to that of ibuprofen or the fixed-dose combinations hydrocodone/paracetamol, codeine/paracetamol and codeine/paracetamol/ibuprofen. In addition, the analgesic efficacy of tramadol/paracetamol did not differ significantly from that of gabapentin in patients with chronic pain associated with diabetic peripheral neuropathy. Tramadol/paracetamol had no additional tolerability issues relative to its components and, overall, the tolerability profile of tramadol/paracetamol was generally similar to that of other active comparators (fixed-dose combinations or single-agents); however, incidences of some adverse events were lower in tramadol/paracetamol than in active comparator recipients. Although additional comparative and long-term studies would help to definitively position tramadol/paracetamol with respect to other analgesics, available clinical data suggest that tramadol/paracetamol is a useful treatment option for providing multimodal analgesia in patients with moderate to severe pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Table V
Table VI
Table VII
Table VIII
Table IX
Table X

Similar content being viewed by others

References

  1. International Association of the Study of Pain. IASP pain terminology: pain [online]. Available from URL: http://www.iasp-pain.org [Accessed 2010 Jun 2]

  2. Langford RM. Pain management today: what have we learned? Clin Rheumatol 2006; 25Suppl. 1: S2–8

    Article  PubMed  Google Scholar 

  3. Varrassi G, Müller-Schwefe G, Pergolizzi J, et al. Pharmacological treatment of chronic pain: the need for CHANGE. Curr Med Res Opin 2010 May; 26(5): 1231–45

    Article  PubMed  CAS  Google Scholar 

  4. Raffa R. Pharmacological aspects of successful long-term analgesia. Clin Rheumatol 2006; 25Suppl. 1: S9–15

    Article  PubMed  Google Scholar 

  5. McClellan K, Scott LJ. Tramadol/paracetamol. Drugs 2003; 63(11): 1079–86; discussion 1087-8

    Article  CAS  Google Scholar 

  6. Mattia C, Coluzzi F, Sarzi Puttini P, et al. Paracetamol/tramadol association: the easy solution for mild-moderate pain. Minerva Med 2008 Aug; 99(4): 369–90

    PubMed  CAS  Google Scholar 

  7. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000; 60(1): 139–76

    Article  PubMed  CAS  Google Scholar 

  8. Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther 2006 Jan; 79(1): 9–19

    Article  PubMed  CAS  Google Scholar 

  9. Anderson BJ. Paracetamol (acetaminophen): mechanisms of action. Paediatr Anaesth 2008 Oct; 18(10): 915–21

    Article  PubMed  Google Scholar 

  10. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther 2005; 12(1): 46–55

    Article  PubMed  Google Scholar 

  11. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43(13): 879–923

    Article  PubMed  CAS  Google Scholar 

  12. Grünenthal Ltd. Tramacet (tramadol/paracetamol) 37.5 mg/325 mg film-coated tablets [online]. Available from URL: http://www.medicines.org.uk/EMC/medicine/22196/SPC/Tramacet+37.5+mg++325+mg+film-coated+tablets/ [Accessed 2010 May 24]

  13. Raffa RB, Friderichs E, Reiman W, et al. Opioid and non-opioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992; 260(1): 275–85

    PubMed  CAS  Google Scholar 

  14. Stamer UM, Stuber F. Pharmacogenomics and perioperative medicine: implications for modern clinical practice [letter]. Can J Anaesth 2009 Jun; 56(6): 467–8; author reply 468

    Article  PubMed  Google Scholar 

  15. Bonnefont J, Courade JP, Alloui A, et al. Antinociceptive mechanism of action of paracetamol [in French]. Drugs 2003; 63 Spec Issue no. 2: 1–4

    Article  PubMed  Google Scholar 

  16. Tallarida RJ, Raffa RB. Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram. Life Sci 1996; 58(2): PL23–8

    Article  CAS  Google Scholar 

  17. Filitz J, Ihmsen H, Gunther W, et al. Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain 2008 Jun; 136(3): 262–70

    Article  PubMed  CAS  Google Scholar 

  18. Pickering G, Estrade M, Dubray C. Comparative trial of tramadol/paracetamol and codeine/paracetamol combination tablets on the vigilance of healthy volunteers. Fundam Clin Pharmacol 2005 Dec; 19(6): 707–11

    CAS  Google Scholar 

  19. Desmeules J, Rollason V, Piguet V, et al. Clinical pharmacology and rationale of analgesic combinations. Eur J Anaesthesiol Suppl. 2003; 28: 7–11

    PubMed  CAS  Google Scholar 

  20. Grünenthal Ltd. Tramacet (tramadol/paracetamol) 37.5/325 mg effervescent tablets [online]. Available from URL: http://www.medicines.org.uk/EMC/medicine/22691/SPC/Tramacet+37.5+mg+325+mg+effervescent+tablets/ [Accessed 2010 Jul 16]

  21. Grünenthal. Public assessment report (scientific discussion): Zaldiar or Ixprim (tramadol/paracetamol) 37.5mg/325mg effervescent tablets (FR/H/211-212/02/DC). Levallois-Perret: Grünenthal, 2008

  22. Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996 Dec; 60(6): 636–44

    Article  PubMed  CAS  Google Scholar 

  23. Fricke JRJ, Karim R, Jordan D, et al. A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetaminophen combination tablets, hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clin Ther 2002 Jun; 24(6): 953–68

    Article  PubMed  CAS  Google Scholar 

  24. Silverfield JC, Kamin M, Wu SC, et al. Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis flare pain: a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. Clin Ther 2002 Feb; 24(2): 282–97

    Article  PubMed  CAS  Google Scholar 

  25. Emkey R, Rosenthal N, Wu SC, 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 Jan; 31(1): 150–6

    PubMed  CAS  Google Scholar 

  26. Bourne MH, Rosenthal NR, Xiang J, et al. Tramadol/acetaminophen tablets in the treatment of postsurgical orthopedic pain [published erratum appears in Am J Orthop 2006 Sep; 35 (9): 410]. Am J Orthop 2005 Dec; 34(12): 592–7

    PubMed  Google Scholar 

  27. Smith AB, Ravikumar TS, Kamin M, et al. Combination tramadol plus acetaminophen for postsurgical pain. Am J Surg 2004 Apr; 187(4): 521–7

    Article  PubMed  CAS  Google Scholar 

  28. Ruoff GE, Rosenthal N, Jordan D, et al. Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter, randomized, double-blind, placebo-controlled outpatient study. Clin Ther 2003 Apr; 25(4): 1123–41

    Article  PubMed  CAS  Google Scholar 

  29. Peloso PM, Fortin L, Beaulieu A, et al. 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 2004 Dec; 31(12): 2454–63

    PubMed  CAS  Google Scholar 

  30. Bennett RM, Kamin M, Karim R, et al. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med 2003 May; 114(7): 537–45

    Article  PubMed  CAS  Google Scholar 

  31. Freeman R, Raskin P, Hewitt DJ, et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy. Curr Med Res Opin 2007 Jan; 23(1): 147–61

    Article  PubMed  CAS  Google Scholar 

  32. Hewitt DJ, Todd KH, Xiang J, et al. Tramadol/acetaminophen or hydrocodone/acetaminophen for the treatment of ankle sprain: a randomized, placebo-controlled trial. Ann Emerg Med 2007 Apr; 49(4): 468–80

    Article  PubMed  Google Scholar 

  33. Perrot S, Krause D, Crozes P, et al. Efficacy and tolerability of paracetamol/tramadol (325mg/37.5mg) combination treatment compared with tramadol (50 mg) monotherapy in patients with subacute low back pain: a multicenter, randomized, double-blind, parallel-group, 10-day treatment study. Clin Ther 2006 Oct; 28(10): 1592–606

    Article  PubMed  CAS  Google Scholar 

  34. Lee EY, Lee EB, Park BJ, et al. Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: a 1-week, randomized, double-blind, placebo-controlled trial. Clin Ther 2006 Dec; 28(12): 2052–60

    Article  PubMed  CAS  Google Scholar 

  35. Fricke JRJ, Hewitt DJ, Jordan DM, et al. A double-blind placebo-controlled comparison of tramadol/acetaminophen and tramadol in patients with postoperative dental pain. Pain 2004 Jun; 109(3): 250–7

    Article  PubMed  CAS  Google Scholar 

  36. Cha BY, Ko KS, Kim DS, et al. Comparison of the analgesic efficacy and safety between tramadol/acetaminophen combination tablet (Ultracet) and gabapentin for the treatment of painful diabetic neuropathy: multicenter, randomized, open comparative study [abstract no. O-0218]}. 20th World Diabetes Congress; 2009 Oct 18–22; Montreal (QC)

  37. Edwards JE, McQuay HJ, Moore RA. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage 2002 Feb; 23(2): 121–30

    Article  PubMed  CAS  Google Scholar 

  38. Mullican WS, Lacy JR. Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther 2001 Sep; 23(9): 1429–45

    Article  PubMed  CAS  Google Scholar 

  39. Silberstein SD, Freitag FG, Rozen TD, et al. Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache 2005 Nov 31; 45(10): 1317–27

    Article  PubMed  Google Scholar 

  40. Rawal N, Langford R, on behalf of the ZAL-06 Study Group. Paracetamol and tramadol combination tablets (Zaldair®) for the treatment of pain in day-care hand surgery patients: a multicentre, randomised, double-blind, double-dummy study [abstract]. 3rd World Congress World Institute of Pain; 2004 Sep 21–25; Barcelona

  41. Jung YS, Kim DK, Kim MK, et al. Onset of analgesia and analgesic efficacy of tramadol/acetaminophen and codeine/acetaminophen/ibuprofen in acute postoperative pain: a single-center, single-dose, randomized, active-controlled, parallel-group study in a dental surgery pain model. Clin Ther 2004 Jul; 26(7): 1037–45

    Article  PubMed  CAS  Google Scholar 

  42. Serrie A, Ganry H, Creuzé A, et al. Données épidémiologiques d’efficacité et de tolérance de l’association fixe paracétamol (325 mg) tramadol (37,5 mg) (Zaldiar®): dans le traitement des douleurs modérées à intenses, en pratique de ville (étude ELZA). Rhumatos 2008 Sep; Book 3, Vol 5(40): 1–12

    Google Scholar 

  43. Serrie A, Jouve E, Creuze A, et al. Efficacy and safety of paracetamol (325 mg)-tramadol (37.5mg) combination (PTC) in elderly patients: a PMS in general practice [abstract no. 616]. Eur J Pain 2009; 13Suppl. 1: S179

    Article  Google Scholar 

  44. Medve RA, Wang J, Karim R. Tramadol and acetaminophen tablets for dental pain. Anesth Prog 2001; 48(3): 79–81

    PubMed  CAS  Google Scholar 

  45. Alwine LK on behalf of the TRAMAP-ANAG-006 Study Group. Long-term (2-year) analgesic efficacy of tramadol/acetaminophen tablets [abstract no. POS-301 plus poster]. Annual European Congress of Rheumatology; 2000 Jun 20-24; Nice

  46. Rosenthal NR, Silverfield JC, Wu SC, et al. Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient population. J Am Geriatr Soc 2004 Mar; 52(3): 374–80

    Article  PubMed  Google Scholar 

  47. Janssen Korea Ltd. A study on the safety and effectiveness of tramadol 37.5 mg/actaminophen 325 mg versus gabapentin in diabetic neuropathic pain [ClinicalTrials.gov identifier NCT00634543]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2010 May 19]

  48. Tavassoli N, Lapeyre-Mestre M, Sommet A, et al. Reporting rate of adverse drug reactions to the French pharmaco-vigilance system with three step 2 analgesic drugs: dextro-propoxyphene, tramadol and codeine (in combination with paracetamol). Br J Clin Pharmacol 2009 Sep; 68(3): 422–6

    Article  PubMed  CAS  Google Scholar 

  49. Choi CB, Song JS, Kang YM, et al. 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. Clin Ther 2007 Jul; 29(7): 1381–9

    Article  PubMed  CAS  Google Scholar 

  50. European Medicines Agency. European Medicines Agency recommends withdrawal of dextropropoxyphene-containing medicines [media release]. 25 Jun 2009 [online]. Available from URL: http://www.ema.europa.eu/pdfs/human/press/pr/40106209en.pdf

  51. World Health Organization. WHO normative guidelines on pain management: report of a Delphi Study to determine the need for guidelines and to identify the number and topics of guidelines that should be developed by WHO [online]. Available from URL: http://www.who.int/medicines/areas/quality_safety/delphi_study_pain_guidelines.pdf [Accessed 2010 Jun 2]

  52. European Society of Regional Anaesthesia and Pain Therapy. Postoperative pain management — good clinical practice: general recommendations and principles for successful pain management [online]. Available from URL: http://www.esraeurope.org/PostoperativePainManagement.pdf [Accessed 2010 Jun 2]

  53. van Tulder M, Becker A, Bekkering T, et al. on behalf of the COST B13 Working Group on guidelines for the management of acute low back pain in primary care. Chapter 3. European guidelines for the management of acute nonspecific low back pain in primary care. Eur Spine J 2006 Mar; 15Suppl. 2: S169–91

    Article  PubMed  Google Scholar 

  54. Schnitzer TJ. Update on guidelines for the treatment of chronic musculoskeletal pain. Clin Rheumatol 2006; 25Suppl. 1: S22–9

    Article  PubMed  Google Scholar 

  55. Luqmani R, Hennell S, Estrach C, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (the first two years). Rheumatology (Oxford) 2006 Sep; 45(9): 1167–9

    Article  CAS  Google Scholar 

  56. Luqmani R, Hennell S, Estrach C, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years). Rheumatology (Oxford) 2009 Apr; 48(4): 436–9

    Article  Google Scholar 

  57. Carville SF, Arendt-Nielsen S, Bliddal H, et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis 2008 Apr; 67(4): 536–41

    Article  PubMed  CAS  Google Scholar 

  58. Evers S, Afra J, Frese A, et al. EFNS guideline on the drug treatment of migraine: revised report of an EFNS task force. Eur J Neurol 2009 Sep; 16(9): 968–81

    Article  PubMed  CAS  Google Scholar 

  59. European Association of Urology. Guidelines on pain management [online]. Available from URL: http://www.uroweb.org/gls/pdf/Pain%20 Management%202010.pdf [Accessed 2010 Jun 2]

  60. Airaksinen O, Brox JI, Cedraschi C on behalf of the COST B13 Working Group on guidelines for chronic low back pain. Chapter 4. European guidelines for the management of chronic nonspecific low back pain. Eur Spine J 2006 Mar; 15Suppl 2: S192–300

    Article  PubMed  Google Scholar 

  61. Jost L, Roila F, on behalf of the ESMO Guidelines Working Group. Management of cancer pain: ESMO clinical recommendations. Ann Oncol 2009 May; 20Suppl. 4: iv170–3

    Article  Google Scholar 

  62. World Health Organization. WHO’s pain ladder [online]. Available from URL: http://www.who.int/cancer/pallia tive/painladder/en/index.html [Accessed 2010 Jun 4]

  63. Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Ther Clin Risk Manage 2007; 3(5): 717–23

    CAS  Google Scholar 

  64. Trescot AM, Datta S, Lee M, et al. Opioid pharmacology. Pain Physician 2008 Mar; 11(2 Suppl.): S133–53

    PubMed  Google Scholar 

  65. Flake ZA, Scalley RD, Bailey AG. Practical selection of antiemetics. Am Fam Physician 2004 Mar 1; 69(5): 1169–74

    PubMed  Google Scholar 

  66. National Institute for Health and Clinical Excellence. Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings [online]. Available from URL: http://www.nice.org.uk/nicemedia/live/12948/47949/47949.pdf [Accessed 2010 Jun 3]

  67. Myles PS, Power I. Clinical update: postoperative analgesia. Lancet 2007 Mar 10; 369(9564): 810–2

    Article  PubMed  Google Scholar 

  68. Schug SA. Combination analgesia in 2005 — a rational approach: focus on paracetamol-tramadol. Clin Rheumatol 2006; 25Suppl. 1: s16–21

    Article  PubMed  Google Scholar 

  69. Raffa RB, Clark-Vetri R, Tallarida RJ, et al. Combination strategies for pain management. Expert Opin Pharmacother 2003 Oct; 4(10): 1697–708

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Adis, a Wolters Kluwer Business, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore,0754, Auckland, New Zealand

    Sohita Dhillon

Authors
  1. Sohita Dhillon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sohita Dhillon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dhillon, S. Tramadol/Paracetamol Fixed-Dose Combination. Clin. Drug Investig. 30, 711–738 (2010). https://doi.org/10.2165/11205830-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11205830-000000000-00000

Keywords

Search

Navigation