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Combination analgesia in 2005—a rational approach: focus on paracetamol–tramadol

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Abstract

A multimodal (or balanced) approach to anaesthesia is a familiar concept that offers important benefits in the management of both acute and chronic pain. Rational combinations of analgesic agents with different mechanisms of action can achieve improved efficacy and/or tolerability and safety compared with equianalgesic doses of the individual drugs. Combining different agents also enhances efficacy in complex pain states that involve multiple causes. Combinations of paracetamol plus a weak opioid agent are widely used. One such combination, paracetamol plus tramadol, exploits the well-established complementary pharmacokinetics and mechanisms of action of these two drugs. This combination has demonstrated genuine synergy in animal studies and also combines paracetamol’s rapid onset of efficacy with tramadol’s prolonged analgesic effect. Numerous studies have confirmed the efficacy and tolerability of paracetamol plus tramadol in both acute and chronic pain. As a single-dose treatment for acute post-operative pain, this combination delivers rapid and sustained pain relief that is greater than either agent alone. There is also extensive evidence for efficacy in the long-term management of chronic pain conditions, including osteoarthritis, low back pain and fibromyalgia. In the setting of chronic pain, paracetamol plus tramadol has shown sustained efficacy, safety and tolerability for up to 2 years without the development of tolerance. The efficacy of this combination has been demonstrated as well in respect to reduction of pain intensity and, more importantly, with regard to improvement of function and quality of life and the reduction of disability. Comparative trials have shown that paracetamol plus tramadol has comparable efficacy to paracetamol plus codeine, but with reduced somnolence and constipation compared with the codeine combination. The paracetamol plus tramadol combination is also free of organ toxicity associated with selective and non-selective non-steroidal anti-inflammatory drugs. Hence, paracetamol plus tramadol offers an effective and well-tolerated alternative to anti-inflammatory drugs or other paracetamol plus weak opioid combinations.

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References

  1. Kaplowitz N (2004) Acetaminophen hepatoxicity: what do we know, what don’t we know, and what do we do next? Hepatology 40:23–26

    Article  PubMed  CAS  Google Scholar 

  2. Hippisley-Cox J, Coupland C (2005) Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. Br Med J 330:1366

    Article  CAS  Google Scholar 

  3. Schug SA, Garrett WR, Gillespie G (2003) Opioid and non-opioid analgesics. Best Pract Res Clin Anaesthesiol 17:91–110

    Article  PubMed  CAS  Google Scholar 

  4. Playford RJ, Vesey DA, Haldane S, Alison MR, Calam J (1991) Dose-dependent effects of fentanyl on indomethacin-induced gastric damage. Digestion 49:198–203

    PubMed  CAS  Google Scholar 

  5. Kehlet H, Dahl JB (1993) The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 77:1048–1056

    Article  PubMed  CAS  Google Scholar 

  6. Aitkinhead AR (2001) Textbook of anaesthesia. Churchill Livingstone, London

    Google Scholar 

  7. Crews JC, Hord AH, Denson DD, Schatzman C (1999) A comparison of the analgesic efficacy of 0.25% levobupivacaine combined with 0.005% morphine, 0.25% levobupivacaine alone, or 0.005% morphine alone for the management of postoperative pain in patients undergoing major abdominal surgery. Anesth Analg 89:1504–1509

    Article  PubMed  CAS  Google Scholar 

  8. Kehlet H, Wilmore DW (2002) Multimodal strategies to improve surgical outcome. Am J Surg 183:630–641

    Article  PubMed  Google Scholar 

  9. Kehlet H, Werner M, Perkins F (1999) Balanced analgesia: what is it and what are its advantages in postoperative pain? Drugs 58:793–797

    Article  PubMed  CAS  Google Scholar 

  10. Scott DA, Blake D, Buckland M et al (1999) A comparison of epidural ropivacaine infusion alone and in combination with 1, 2, and 4 microg/ml fentanyl for seventy-two hours of postoperative analgesia after major abdominal surgery. Anesth Analg 88:857–864

    Article  PubMed  CAS  Google Scholar 

  11. Moizo E, Berti M, Marchetti C et al (2004) Acute pain service and multimodal therapy for postsurgical pain control: evaluation of protocol efficacy. Minerva Anestesiol 70:779–787

    PubMed  CAS  Google Scholar 

  12. Schug SA, Sidebotham DA, McGuinnety M, Thomas J, Fox L (1998) Acetaminophen as an adjunct to morphine by patient-controlled analgesia in the management of acute postoperative pain. Anesth Analg 87:368–372

    Article  PubMed  CAS  Google Scholar 

  13. Hyllested M, Jones S, Pedersen JL, Kehlet H (2002) Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 88:199–214

    Article  PubMed  CAS  Google Scholar 

  14. Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR (1996) Morphine consumption in patients receiving rectal paracetamol and diclofenac alone and in combination. Br J Anaesth 77:445–447

    PubMed  CAS  Google Scholar 

  15. Macleod AG, Ashford B, Voltz M et al (2002) Paracetamol versus paracetamol-codeine in the treatment of post-operative dental pain: a randomized, double-blind, prospective trial. Aust Dent J 47:147–151

    Article  PubMed  Google Scholar 

  16. Fricke JR Jr, Karim R, Jordan D, Rosenthal N (2002) 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 24:953–968

    Article  PubMed  CAS  Google Scholar 

  17. Li Wan Po A, Zhang WY (1997) Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. Br Med J 315:1565–1571

    CAS  Google Scholar 

  18. Medicines and Healthcare products Regulatory Agency. MHRA withdraws the pain killer co-proxamol. Press release 21 January 2005. Downloaded November 2005. http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON002065&ssTargetNodeId=389

  19. Tallarida RJ, Raffa RB (1996) Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram. Life Sci 58:PL23–PL28

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Ruoff GE, Rosenthal N, Jordan D, Karim R, Kamin M; Protocol CAPSS-112 Study Group (2003) Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter, randomized, double-blind, placebo-controlled outpatient study. Clin Ther 25:1123–1141

    Article  PubMed  CAS  Google Scholar 

  23. Alwine LK (2000) Long-term (2-year) analgesic efficacy of tramadol/acetaminophen tablets. Ann Rheum Dis 59(Suppl 1):136

    Google Scholar 

  24. Prescott LF (2000) Therapeutic misadventure with paracetamol: fact or fiction? Am J Ther 7:99–114

    Article  PubMed  CAS  Google Scholar 

  25. Edwards JE, McQuay HJ, Moore RA (2002) Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain. J Pain Symptom Manage 23:121–130

    Article  PubMed  CAS  Google Scholar 

  26. Perrot S, Krause D (2002) Comparaison de la tolérance des traitements et de la satisfaction des patients traités par l’association tramadol (37,5 mg)–paracetamol (325 mg) et du tramadol (50 mg) seul pour lombalgies subaiguës. Douleurs 3(Suppl 1):2S55

    Google Scholar 

  27. Silverfield 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. Clin Ther 24:282–297

    Article  PubMed  CAS  Google Scholar 

  28. European Medicines Agency Press office (2005) Press release European Medicines Agency concludes action on COX-2 inhibitors. Doc. Ref. EMEA/207766/2005. Downloaded from: http://www.emea.eu.int/pdfs/human/press/pr/20776605en.pdf

  29. US Food and Drugs Administration (FDA) Center for Drug Evaluation and Research (2005) FDA Public Health Advisory. FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Downloaded from: http://www.fda.gov/cder/drug/advisory/COX2.htm

  30. 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 antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. J Rheumatol 31:150–156

    PubMed  CAS  Google Scholar 

  31. 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 31:2454–2463

    PubMed  CAS  Google Scholar 

  32. Peloso PM, Rosenthal N, Jordan D, Karim R (2003) Tramadol/acetaminophen combination tablets (Ultracet) for chronic lower back pain: pooled analysis. J Pain 4(2 Suppl 1):26

    Google Scholar 

  33. Rosenthal N, Peloso P, Jordan D, Karim R (2002) A pooled analysis of the efficacy and safety of tramadol/acetaminophen combination tablets (Ultracet) in chronic lower back pain: quality of life measures. Arthritis Rheum 46(9 Suppl):S107

    Google Scholar 

  34. Mullican WS, Lacy JR; TRAMAP-ANAG-006 Study Group (2001) Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the management of chronic pain: a comparative trial. Clin Ther 23:1429–1445

    Article  PubMed  CAS  Google Scholar 

  35. Staud R (2002) Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Curr Rheumatol Rep 4:299–305

    Article  PubMed  Google Scholar 

  36. Kosek E, Ekholm J, Hansson P (1996) Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 68:375–383

    Article  PubMed  CAS  Google Scholar 

  37. Bennett RM (1999) Emerging concepts in the neurobiology of chronic pain: evidence of abnormal sensory processing in fibromyalgia. Mayo Clin Proc 74:385–398

    Article  PubMed  CAS  Google Scholar 

  38. Yunus MB, Masi AT, Aldag JC (1989) Short-term effects of ibuprofen in primary fibromyalgia syndrome: a double blind, placebo-controlled trial. J Rheumatol 16:527–532

    PubMed  CAS  Google Scholar 

  39. Duhmke RM, Cornblath DD, Hollingshead JR (2004) Tramadol for neuropathic pain. Cochrane Database Syst Rev CD003726

  40. Bennett RM, Kamin M, Karim R, Rosenthal N (2003) Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med 114:537–545

    Article  PubMed  CAS  Google Scholar 

  41. Granges G, Zilko P, Littlejohn GO (1994) Fibromyalgia syndrome: Assessment of the severity of the condition 2 years after diagnosis. J Rheumatol 21:523–529

    PubMed  CAS  Google Scholar 

  42. Bennett RM, Schein J, Kosinski MR, Hewitt DJ, 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

    Article  PubMed  Google Scholar 

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Disclosures/financial interests

The author has received research funding and consultant fees from Bristol Myers Squibb, Grünenthal and Pfizer.

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  1. School of Medicine and Pharmacology, The University of Western Australia, Level 2, MRF Building G Block Royal Perth Hospital, GPO Box X2213, Perth, WA, 6847, Australia

    Stephan A. Schug

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Correspondence to Stephan A. Schug.

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Schug, S.A. Combination analgesia in 2005—a rational approach: focus on paracetamol–tramadol. Clin Rheumatol 25 (Suppl 1), 16–21 (2006). https://doi.org/10.1007/s10067-006-0202-9

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