Skip to main content

Advertisement

SpringerLink
Log in

Pharmacological aspects of successful long-term analgesia

  • Review
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Persistent pain represents a major quality-of-life burden for patients and a challenge for their physician. Chronic pain often arises from multiple tissue sources and involves multiple chemical mediators and pain transmission pathways. Successful long-term pain management requires analgesic regimens that can treat pains of multiple origin and type. Safety and tolerability are also a high priority when prescribing chronic therapy. Recent publications and regulatory developments affecting anti-inflammatory drugs have limited the options available for the management of chronic pain. Major concerns in long-term use of anti-inflammatory drugs include renal toxicity, gastrointestinal ulceration and bleeding and cardiovascular events, which can be of particular concern for elderly patients. Opioid agents avoid the end-organ toxicity seen with anti-inflammatory drugs, but their use may be limited, especially in the long term, by side effects such as constipation or sedation and by concerns about the potential for physical or psychological dependence. Paracetamol (acetaminophen) has a favourable safety and tolerability profile, although exceeding the recommended dose (up to 4 g/day) carries a risk of liver damage. It exerts simultaneous anti-nociception at both spinal and supra-spinal sites, and has shown self-synergy between these two routes of activity. Tramadol, an atypical weak opioid with a multi-modal mechanism of action, inhibits re-uptake of multiple neurotransmitters and has an improved safety and tolerability profile compared with traditional opioids. Rational combinations of analgesic drugs offer a viable approach to managing persistent pain that involves multiple sites or pathways. The combination of paracetamol plus tramadol brings together two well-known analgesics that have different but complementary mechanisms of analgesic action. Laboratory studies have demonstrated that these agents interact to produce synergistic analgesia with a desirable safety/efficacy profile.

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

Fig. 1 a,b
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Smith BH, Elliott AM, Chambers WA, Smith WC, Hannaford PC, Penny K (2001) The impact of chronic pain in the community. Fam Pract 18:292–299

    Article  PubMed  CAS  Google Scholar 

  2. Hawkey CJ (1999) COX-2 inhibitors. Lancet 353:307–314

    Article  PubMed  CAS  Google Scholar 

  3. Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437

    Article  PubMed  CAS  Google Scholar 

  4. Komhoff M, Grone HJ, Klein T, Seyberth HW, Nusing RM (1997) Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function. Am J Physiol 272:F460–F468

    PubMed  CAS  Google Scholar 

  5. Lanas A, Perez-Asia MA, Feu F et al (2005) on behalf of the Investigators of the Asociación Española de Gastroenterología. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory use. Am J Gastroenterol 100:1685–1693

    Article  PubMed  CAS  Google Scholar 

  6. Smalley WE, Ray WA, Daugherty JR et al (1995) Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J Epidemiol 141:539–545

    PubMed  CAS  Google Scholar 

  7. Cronstein B (2002) Cyclooxygenase-2-selective inhibitors: Translating pharmacology into clinical utility. Cleve Clin J Med 69(Suppl 1):S1–S19

    Google Scholar 

  8. Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954–959

    Article  PubMed  CAS  Google Scholar 

  9. Solomon DH, Schneeweiss S, Levin R, Avorn J (2004) Relationship between COX-2 specific inhibitors and hypertension. Hypertension 44:140–145

    Article  PubMed  CAS  Google Scholar 

  10. US FDA memorandum (NDA 21-042, S-007). Cardiovascular safety review, February 1, 2001 http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf. Accessed November 2005

  11. US FDA Press release, 30 September 2004. FDA issues public health advisory on Vioxx as its manufacturer voluntarily withdraws the product. http://www.fda.gov/bbs/topics/news/2004/NEW01122.html. Accessed November 2005

  12. US FDA memorandum, April 6, 2005. http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf. Accessed November 2005

  13. EMEA Press release, 17 October 2005. European Medicines Agency update on non-selective NSAIDs. http://www.emea.eu.int/htms/hotpress/h29896405.htm. Accessed November 2005

  14. US FDA alert, 04/07/05. Valdecoxib (marketed as Bextra). http://www.fda.gov/cder/drug/InfoSheets/HCP/valdecoxibHCP.pdf. Accessed November 2005

  15. EMEA statement, 7 April 2005. European Medicines Agency statement on the suspension of use of Bextra. http://www.emea.eu.int/htms/hotpress/h12163705.htm. Accessed November 2005

  16. EMEA Press release, 27 June 2005. European Medicines Agency concludes action on COX-2 inhibitors. http://www.emea.eu.int/pdfs/human/press/pr/20776605en.pdf. Accessed November 2005

  17. EMEA Press release, 2 August 2005. http://www.emea.eu.int/pdfs/human/press/pr/24732305en.pdf. Accessed November 2005

  18. Prior MJ, Cooper KM, May LG, Bowen DL (2002) Efficacy and safety of acetaminophen and naproxen in the treatment of tension-type headache. A randomized, double-blind, placebo-controlled trial. Cephalalgia 22:740–748

    Article  PubMed  CAS  Google Scholar 

  19. Lipton RB, Baggish JS, Stewart WF, Codispoti JR, Fu M (2000) Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, population-based study. Arch Intern Med 160:3486–3492

    Article  PubMed  CAS  Google Scholar 

  20. Stannard C, Booth S (2004) Pain. Elsevier-Churchill Livingstone, London

    Google Scholar 

  21. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines (2000). Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 43:1905–1915

    Article  Google Scholar 

  22. Von Mering J (1893) Beiträge zur Kenntniss der Antipyretica. Therap Monatshefte 7:577–578

    Google Scholar 

  23. Raffa RB, Stone DJ Jr, Tallarida RJ (2000). Discovery of “self-synergistic” spinal/supraspinal antinociception produced by acetaminophen (paracetamol). J Pharmacol Exp Ther 295:291–294

    PubMed  CAS  Google Scholar 

  24. Raffa RB, Codd EE (1996) Lack of binding of acetaminophen to 5-HT receptor or uptake sites (or eleven other binding/uptake assays). Life Sci 59:PL37–PL40

    Article  PubMed  CAS  Google Scholar 

  25. Raffa RB et al (2005) Netter’s illustrated pharmacology. Icon Learning Systems, Teterboro, NJ

    Google Scholar 

  26. VA/DoD clinical practice guideline for the management of opioid therapy for chronic pain. Downloaded from: http://www.oqp.med.va.gov/cpg/cot/ot_base.htm; summary at: http://www.oqp.med.va.gov/cpg/cot/G/OT_Sum.pdf. September 2003. Accessed November 2005

  27. Auret K, Schug SA (2005) Underutilisation of opioids in elderly patients with chronic pain. Drugs Aging 22:641–654

    Article  PubMed  CAS  Google Scholar 

  28. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992) Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 260:275–285

    PubMed  CAS  Google Scholar 

  29. Bamigbade TA, Davidson C, Langford RM, Stamford JA (1997) Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 79:352–356

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. FDA Public Health Advisory, 7 April 2005. FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) http://www.fda.gov/cder/drug/advisory/COX2.htm. Accessed November 2005

  32. Committee on Safety of Medicines 2005. Current Problems in Pharmacovigilance. Volume 30, October 2004. Downloaded from: http://www.mca.gov.uk/aboutagency/regframework/csm/csmhome.htm / http://medicines.mhra.gov.uk/ourwork/monitor safequalmed/currentproblems/currentproblems.htm

  33. Schou J, Angelo H, Dam W, Jensen K, Christensen JM (1978) Pharmacokinetics of dextropropoxyphene in acute poisoning. Arch Toxicol Suppl 1:343–346

    PubMed  Google Scholar 

  34. Gibson TP, Giacomini KM, Briggs WA, Whitman W, Levy G (1980) Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient. Clin Pharmacol Ther 27:665–670

    Article  PubMed  CAS  Google Scholar 

  35. Sloth Madsen P, Strom J, Reiz S, Bredgaard Sorensen M (1984) Acute propoxyphene self-poisoning in 222 consecutive patients. Acta Anaesthesiol Scand 28:661–665

    PubMed  CAS  Google Scholar 

  36. Crome P, Gain R, Ghurye R, Flanagan RJ (1984) Pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in elderly hospital patients after single and multiple doses of distalgesic. Preliminary analysis of results. Hum Toxicol 3:41S–48S (Suppl)

    Article  PubMed  Google Scholar 

  37. Flanagan RJ, Johnston A, White AS, Crome P (1989) Pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in young and elderly volunteers after single and multiple dextropropoxyphene dosage. Br J Clin Pharmacol 28:463–469

    PubMed  CAS  Google Scholar 

  38. Pearson RM (1984) Pharmacokinetics of propoxyphene. Hum Toxicol 3:37S–40S (Suppl)

    Article  PubMed  Google Scholar 

  39. Cascorbi I (2003) Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication. Eur J Clin Invest 33(Suppl 2):17–22

    Article  PubMed  CAS  Google Scholar 

  40. Schnitzer T (2003) The new analgesic combination tramadol/acetaminophen. Eur J Anaesthesiol 28:13–17 (Suppl)

    CAS  Google Scholar 

  41. 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 

  42. 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 

  43. 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 

  44. 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 

  45. 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 

  46. 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 

  47. Smith AB, Ravikumar TS, Kamin M, Jordan D, Xiang J, Rosenthal N, CAPSS-115 Study Group (2004) Combination tramadol plus acetaminophen for postsurgical pain. Am J Surg 187:521–527

    Article  PubMed  CAS  Google Scholar 

  48. Fricke JR, Karim R, Jordan D, Rosenthal N (2002) A double-blind, single-dose comparison of the analgesic efficacy of tramadol/acetominophen combination tablets, and placebo, after surgery. Clin Ther 24:953–968

    Article  PubMed  CAS  Google Scholar 

  49. 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 

  50. 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 

  51. 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. BMJ 330:1366

    Article  PubMed  CAS  Google Scholar 

  52. US FDA information page, April 7, 2005. COX-2 selective (includes Bextra, Celebrex, and Vioxx) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). http://www.fda.gov/cder/drug/infopage/COX2/default.htm. Accessed November 2005

Download references

Acknowledgement

The author greatly appreciates the assistance of Shari Barber in the preparation of this manuscript.

Disclosures/financial interests Dr Raffa is a consultant for Grünenthal and has conducted Grünenthal-sponsored basic science studies.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 N. Broad Street, Suite 540, Philadelphia, PA, 19140-5101, USA

    Robert Raffa

Authors
  1. Robert Raffa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Raffa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Raffa, R. Pharmacological aspects of successful long-term analgesia. Clin Rheumatol 25 (Suppl 1), 9–15 (2006). https://doi.org/10.1007/s10067-006-0201-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-006-0201-x

Keywords

Search

Navigation