Clinical Rheumatology

, Volume 25, Supplement 1, pp 2–8 | Cite as

Pain management today—what have we learned?

Review

Abstract

Pain is a leading cause of morbidity worldwide, with published data showing its prevalence as high as 50% for chronic pain in the European population. This prevalence is likely to continue to rise, particularly in elderly people with comorbid conditions and complex aetiologies of pain. There is thus a rapidly growing demand for safe and effective pain management. Management of mild-to-moderate pain has traditionally been based upon the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the synthetic non-opioid analgesic paracetamol (acetaminophen), the latter of which acts centrally, inhibiting brain cyclo-oxygenase (COX) and nitric oxide synthase. Both the NSAIDs and paracetamol are effective for mild-to-moderate pain and are widely recommended and used. However, NSAIDs may not be tolerated due to gastrointestinal (GI) symptoms and can result in potentially fatal peptic ulceration and bleeding. Selective COX-2 inhibitors were developed to reduce the GI side effects and complications, but large-scale studies have highlighted another serious potential effect of anti-inflammatory drugs: cardiovascular events. Both the European Medicines Agency (EMEA) and the Food and Drugs Administration (FDA) in the US have issued advice to apply cautions and restrictions when prescribing COX-2 inhibitors, particularly for patients at increased cardiovascular risk and for long-term use. The FDA also applied cardiovascular warnings with regard to nonselective NSAIDs. Both the EMEA and the FDA have recommended using the lowest effective dose for the shortest duration. These concerns and warnings have left physicians seeking safe alternatives to anti-inflammatory drugs for both short- and long-term uses in many patients. These developments have generated a climate of uncertainty in the absence of official guidance on the selection of alternative analgesic regimens. Amongst the possible strategies, combinations of drugs that provide analgesic efficacy at reduced individual doses may confer the optimal risk–benefit ratio for pain management in the long term or in patients at increased cardiovascular risk. Weak opioids devoid of serious organ-damaging effects combined with paracetamol may well be safer for long-term therapy. Fixed-dose combinations of paracetamol with weak opioids, such as codeine, dextropropoxyphene or tramadol are currently available. Paracetamol plus tramadol is an effective and safe multimodal analgesic regimen for the management of both acute and chronic moderate-to-severe pain. Re-evaluating the role of weak opioids, such as tramadol, and combinations in pain management may prove a valuable option for prescribers seeking alternatives to anti-inflammatory drugs.

Keywords

Combination COX-2 inhibitor Multiple pathways NSAID Pain management Paracetamol plus codeine Paracetamol plus dextropropoxyphene Paracetamol plus tramadol Tolerability Weak opioid 

Notes

Disclosures/financial interests

Dr. Langford is a consultant for Grünenthal.

References

  1. 1.
    Bassols A, Bosch F, Banos JE (2002) How does the general population treat their pain? A survey in Catalonia, Spain. J Pain Symptom Manage 23:318–328PubMedCrossRefGoogle Scholar
  2. 2.
    Eriksen J, Jensen MK, Sjogren P, Ekholm O, Rasmussen NK (2003) Epidemiology of chronic non-malignant pain in Denmark. Pain 106:221–228PubMedCrossRefGoogle Scholar
  3. 3.
    Català E, Reig E, Artes M, Aliaga L, Lopez, Segu JL (2002) Prevalence of pain in the Spanish population: telephone survey in 5000 homes. Eur J Pain 6:133–140PubMedCrossRefGoogle Scholar
  4. 4.
    Elliott AM, Smith BH, Penny KI, Smith WC, Chambers WA (1999) The epidemiology of chronic pain in the community. Lancet 354:1248–1252PubMedCrossRefGoogle Scholar
  5. 5.
    Smith BH, Elliott AM, Chambers WA, Smith WC, Hannaford PC, Penny K (2001) The impact of chronic pain in the community. Fam Pract 18:292–299PubMedCrossRefGoogle Scholar
  6. 6.
    Centers for Disease Control (2003) Public health and aging: projected prevalence of self-reported arthritis or chronic joint symptoms among persons aged >65 years: United states, 2005–2030. MMWR Morb Mortal Wkly Rep 52:489–491Google Scholar
  7. 7.
    Centers for Disease Control (2005) MMWR Morb Mortal Wkly Rep 54:113–139Google Scholar
  8. 8.
    Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053PubMedCrossRefGoogle Scholar
  9. 9.
    Leveille SG (2004) Musculoskeletal aging. Curr Opin Rheumatol 16:114–118PubMedCrossRefGoogle Scholar
  10. 10.
    EMEA (2004) EMEA to review COX-2 inhibitors. Press release, 22 October 2004. http://www.emea.eu.int/pdfs/human/press/pr/11790804en.pdf. Accessed November 2005
  11. 11.
    EMEA (2005) Press release, 2 August 2005. http://www.emea.eu.int/pdfs/human/press/pr/24732305en.pdf. Accessed November 2005
  12. 12.
    FDA (2004) FDA issues public health advisory recommending limited use of COX-2 inhibitors: agency requires evaluation of prevention studies involving COX-2 selective agents. Talk paper, 23 December 2004. http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01336.html . Accessed November 2005
  13. 13.
    US Food and Drugs Administration (FDA) Center for Drug Evaluation and Research (2005) FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). FDA Public Health Advisory, 7 April 2005. http://www.fda.gov/cder/drug/advisory/COX2.htm. Accessed November 2005
  14. 14.
    Barden J, Edwards JE, McQuay HJ, Wiffen PJ, Moore RA (1997) Relative efficacy of oral analgesics after third molar extraction. Br Dent J 197:407–411CrossRefGoogle Scholar
  15. 15.
    Boureau F, Legallicier P, Kabir-Ahmadi M (2003) Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain 104:323–331PubMedCrossRefGoogle Scholar
  16. 16.
    Milsom I, Minic M, Dawood MY et al (2002) Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies. Clin Ther 24:1384–1400PubMedCrossRefGoogle Scholar
  17. 17.
    Chang DJ, Fricke JR, Bird SR, Bohidar NR, Dobbins TW, Geba GP (2001) Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial. Clin Ther 23:1446–1455PubMedCrossRefGoogle Scholar
  18. 18.
    Daniels SE, Talwalker S, Torri S, Snabes MC, Recker DP, Verburg KM (2002) Valdecoxib, a cyclooxygenase-2-specific inhibitor, is effective in treating primary dysmenorrhea. Obstet Gynecol 100:350–358PubMedCrossRefGoogle Scholar
  19. 19.
    Watcha MF, Issioui T, Klein KW, White PF (2003) Costs and effectiveness of rofecoxib, celecoxib, and acetaminophen for preventing pain after ambulatory otolaryngologic surgery. Anesth Analg 96:987–994PubMedCrossRefGoogle Scholar
  20. 20.
    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 22:740–748PubMedCrossRefGoogle Scholar
  21. 21.
    Jenkins C, Costello J, Hodge L (2004) Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. Br Med J 328:434CrossRefGoogle Scholar
  22. 22.
    Langman MJ, Morgan L, Worrall A (1985) Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. Br Med J 290:347–349CrossRefGoogle Scholar
  23. 23.
    Ruigomez A, Garcia Rodriguez LA, Wallander MA, Johansson S, Graffner H, Dent J (2004) Natural history of gastro-oesophageal reflux disease diagnosed in general practice. Aliment Pharmacol Ther 20:751–760PubMedCrossRefGoogle Scholar
  24. 24.
    Hayashi Y, Yamamoto H, Kita H et al (2005) Non-steroidal anti-inflammatory drug-induced small bowel injuries identified by double-balloon endoscopy. World J Gastroenterol 11:4861–4864PubMedGoogle Scholar
  25. 25.
    Stiel D (2000) Exploring the link between gastrointestinal complications and over-the-counter analgesics: current issues and considerations. Am J Ther 7:91–98PubMedGoogle Scholar
  26. 26.
    Lazzaroni M, Bianchi Porro G (2004) Gastrointestinal side effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment Pharmacol Ther 20(Suppl 2):48–58CrossRefGoogle Scholar
  27. 27.
    National Center for Health Statistics (1998)Google Scholar
  28. 28.
    Singh G, Triadafilopoulos G (1999) Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol 26(Suppl 56):18–24Google Scholar
  29. 29.
    Office for National Statistics (1997)Google Scholar
  30. 30.
    Tramer MR, Moore RA, Reynolds DJ, McQuay HJ (2000) Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 85:169–182PubMedCrossRefGoogle Scholar
  31. 31.
    Strom BL, Schinnar R, Bilker WB, Feldman H, Farrar JT, Carson JL (1997) Gastrointestinal tract bleeding associated with naproxen sodium vs ibuprofen. Arch Intern Med 157:2626–2631PubMedCrossRefGoogle Scholar
  32. 32.
    Hawkey CJ, Langman MJS (2003) Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors. Gut 52:600–608PubMedCrossRefGoogle Scholar
  33. 33.
    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 141:539–545PubMedGoogle Scholar
  34. 34.
    Bombardier C, Laine L, Reicin A et al (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343:1520–1528PubMedCrossRefGoogle Scholar
  35. 35.
    Deeks JJ, Smith LA, Bradley MD (2002) Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Br Med J 325:619CrossRefGoogle Scholar
  36. 36.
    Simon LS, Weaver AL, Graham DY et al (1999) Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 282:1921–1928PubMedCrossRefGoogle Scholar
  37. 37.
    Layton D, Wilton LV, Shakir SA (2004) Safety profile of celecoxib as used in general practice in England: results of a prescription–event monitoring study. Eur J Clin Pharmacol 60:489–501PubMedCrossRefGoogle Scholar
  38. 38.
    Mamdani M, Juurlink DN, Kopp A, Naglie G, Austin PC, Laupacis A (2004) Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. Br Med J 328:1415–1416CrossRefGoogle Scholar
  39. 39.
    MacDonald TM, Pettitt D, Lee FH, Schwartz JS (2003) Channelling of patients taking NSAIDs or cyclooxygenase-2-specific inhibitors and its effect on interpretation of outcomes. Rheumatology (Oxford) 42(Suppl 3):iii3–iii10Google Scholar
  40. 40.
    Rostom A, Dube C, Wells G et al (2002) Prevention of NSAID-induced gastroduodenal ulcers. The Cochrane Database of Systematic Reviews 2002, issue 4, art. no. CD002296. DOI 10.1002/14651858.CD002296Google Scholar
  41. 41.
    Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D (2004) The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. Br Med J 329:948CrossRefGoogle Scholar
  42. 42.
    Ahmad SR, Kortepeter C, Brinker A, Chen M, Beitz J (2002) Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf 25:537–544PubMedCrossRefGoogle Scholar
  43. 43.
    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 330:1366CrossRefGoogle Scholar
  44. 44.
    Cheng HF, Harris RC (2004) Cyclooxygenases, the kidney, and hypertension. Hypertension 43:525–530PubMedCrossRefGoogle Scholar
  45. 45.
    Aw TJ, Haas SJ, Liew D, Krum H (2005) Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med 165:490–496PubMedCrossRefGoogle Scholar
  46. 46.
    Weiss HJ, Aledort LM, Kochwa S (1968) The effect of salicylates on the hemostatic properties of platelets in man. J Clin Invest 47:2169–2180PubMedGoogle Scholar
  47. 47.
    APT Statistical Secretariat (1994) Collaborative overview of randomised trials of antiplatelet therapy—III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Br Med J 308:235–246Google Scholar
  48. 48.
    Hennekens CH, Dyken ML, Fuster V (1997) Aspirin as a therapeutic agent in cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 96:2751–2753PubMedGoogle Scholar
  49. 49.
    Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE (2001) Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 85:265–271PubMedCrossRefGoogle Scholar
  50. 50.
    Lanas A, Perez-Asia MA, Feu F et al (on behalf of the Investigators of the Asociación Española de Gastroenterología) (2005) A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory use. Am J Gastroenterol 100:1685–1693PubMedCrossRefGoogle Scholar
  51. 51.
    Derry S, Loke YK (2000) Risk of gastrointestinal haemorrhage with long-term use of aspirin: meta-analysis. Br Med J 321:1183–1187CrossRefGoogle Scholar
  52. 52.
    Nelson MR, Liew D, Bertram M, Vos T (2005) Epidemiological modelling of routine use of low dose aspirin for the primary prevention of coronary heart disease and stroke in those aged > or =70. Br Med J 330:1306CrossRefGoogle Scholar
  53. 53.
    Capone ML, Tacconelli S, Sciulli MG et al (2004) Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 109:1468–1471PubMedCrossRefGoogle Scholar
  54. 54.
    Catella-Lawson F, Reilly MP, Kapoor SC et al (2001) Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345:1809–1817PubMedCrossRefGoogle Scholar
  55. 55.
    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 160:3486–3492PubMedCrossRefGoogle Scholar
  56. 56.
    Raffa RB, Stone DJ Jr, Tallarida RJ (2000) Discovery of “self-synergistic” spinal/supraspinal antinociception produced by acetaminophen (paracetamol). J Pharmacol Exp Ther 295:291–294PubMedGoogle Scholar
  57. 57.
    Forbes JA, Bates JA, Edquist IA et al (1994) Evaluation of two opioid-acetaminophen combinations and placebo in postoperative oral surgery pain. Pharmacotherapy 14:139–146PubMedGoogle Scholar
  58. 58.
    Gammaitoni AR, Galer BS, Lacouture P, Domingos J, Schlagheck T (2003) Effectiveness and safety of new oxycodone/acetaminophen formulations with reduced acetaminophen for the treatment of low back pain. Pain Med 4:21–30PubMedCrossRefGoogle Scholar
  59. 59.
    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 87:368–372PubMedCrossRefGoogle Scholar
  60. 60.
    Hawton K, Ware C, Mistry H et al (1996) Paracetamol self-poisoning: characteristics, prevention and harm reduction. Br J Psychiatry 168:43–48PubMedGoogle Scholar
  61. 61.
    Kuffner EK, Dart RC, Bogdan GM, Hill RE, Casper E, Darton L (2001) Effect of maximal daily doses of acetominophen on the liver of alcoholic patients. Arch Intern Med 161:2247–2252PubMedCrossRefGoogle Scholar
  62. 62.
    Thummel KE, Slattery JT, Ro H et al (2000) Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther 67:591–599PubMedCrossRefGoogle Scholar
  63. 63.
    Scottish Intercollegiate Guidelines Network (SIGN) (2000) Publication number 44. Control of pain in patients with cancer. A national clinical guidelineGoogle Scholar
  64. 64.
    Schug SA, Zech D, Grond S (1992) Adverse effects of systemic opioid analgesics. Drug Saf 7:200–213PubMedCrossRefGoogle Scholar
  65. 65.
    Schug SA, Garrett WR, Gillespie G (2003) Opioid and non-opioid analgesics. Best Pract Res Clin Anaesthesiol 17:91–110PubMedCrossRefGoogle Scholar
  66. 66.
    Raffa RB (2001) Pharmacology of oral combination analgesics: rational therapy for pain. J Clin Pharm Ther 26:257–264PubMedCrossRefGoogle Scholar
  67. 67.
    Raffa RB, Clarc-Vetri R, Tallarida RJ, Wertheimer AI (2003) Combination strategies for pain management. Expert Opin Pharmacother 4:1697–1708PubMedCrossRefGoogle Scholar
  68. 68.
    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 70:779–787PubMedGoogle Scholar
  69. 69.
    Cobby TF, Crighton IM, Kyriakides K, Hobbs GJ (1999) Rectal paracetamol has a significant morphine-sparing effect after hysterectomy. Br J Anaesth 83:253–256PubMedGoogle Scholar
  70. 70.
    EMEA (2005) European Medicines Agency announces regulatory action on COX-2 inhibitors. Public statement, 17 February 2005. http://www.emea.eu.int/htms/hotpress/d6275705.htm. Accessed November 2005
  71. 71.
    Christie MJ, Vaughan CW, Ingram SL (1999) Opioids, NSAIDs, and 5-lipoxygenase inhibitors act synergistically in brain via arachidonic acid metabolism. Inflamm Res 48:1–4PubMedCrossRefGoogle Scholar
  72. 72.
    Christie MJ, Connor M, Vaughan CW et al (2000) Cellular actions of opioids and other analgesics: implications for synergism in pain relief. Clin Exp Pharmacol Physiol 27:520–523PubMedCrossRefGoogle Scholar
  73. 73.
    Vaughan CW (1998) Enhancement of opioid inhibition of GABAergic synaptic transmission by cyclo-oxygenase inhibitors in rat periaqueductal grey neurones. Br J Pharmacol 123:1479–1481PubMedCrossRefGoogle Scholar
  74. 74.
    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 23:1429–1445PubMedCrossRefGoogle Scholar
  75. 75.
    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 25:1123–1141PubMedCrossRefGoogle Scholar
  76. 76.
    Smith AB, Ravikumar TS, Kamin M et al (2004) Combination tramadol plus acetaminophen for postsurgical pain. Am J Surg 187:521–527PubMedCrossRefGoogle Scholar
  77. 77.
    de Craen AJ, Di Giulio G, Lampe-Schoemaeckers JE, Kessels AG, Kleijnen J (1996) Analgesic efficacy and safety of paracetamol–codeine combinations versus paracetamol alone: a systematic review. Br Med J 313:321–325Google Scholar
  78. 78.
    Cascorbi I (2003) Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication. Eur J Clin Invest 33(Suppl 2):17–22PubMedCrossRefGoogle Scholar
  79. 79.
    Gasche Y, Daali Y, Fathi M et al (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351:2827–2831PubMedCrossRefGoogle Scholar
  80. 80.
    Moore RA, McQuay HJ (1997) Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain 69:287–294PubMedCrossRefGoogle Scholar
  81. 81.
    Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS (2005) Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2:e164PubMedCrossRefGoogle Scholar
  82. 82.
    Collins M, Young I, Sweeney P et al (1997) The effect of tramadol on dento-alveolar surgical pain. Br J Oral Maxillofac Surg 35:54–58PubMedCrossRefGoogle Scholar
  83. 83.
    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 79:352–356PubMedGoogle Scholar
  84. 84.
    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 114:537–545PubMedCrossRefGoogle Scholar
  85. 85.
    Bamigbade TA, Langford RM (1998) The clinical use of tramadol hydrochloride. Pain Rev 5:155–183CrossRefGoogle Scholar
  86. 86.
    Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879–923PubMedCrossRefGoogle Scholar
  87. 87.
    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 23:121–130PubMedCrossRefGoogle Scholar
  88. 88.
    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 31:150–156PubMedGoogle Scholar
  89. 89.
    MHRA (2005) MHRA withdraws the pain killer co-proxamol. MHRA press release, 21 January 2005. http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON002065&ssTargetNodeId=389. Accessed November 2005
  90. 90.
    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 315:1565–1571Google Scholar
  91. 91.
    Sloth Madsen P, Strom J, Reiz S, Bredgaard Sorensen M (1984) Acute propoxyphene self-poisoning in 222 consecutive patients. Acta Anaesthesiol Scand 28:661–665PubMedCrossRefGoogle Scholar
  92. 92.
    Schou J, Angelo H, Dam W, Jensen K, Christensen JM (1978) Pharmacokinetics of dextropropoxyphene in acute poisoning. Arch Toxicol Suppl 1:343–346PubMedGoogle Scholar
  93. 93.
    Kaa E, Dalgaard JB (1989) Fatal dextropropoxyphene poisonings in Jutland, Denmark. Z Rechtsmed 102:107–115PubMedGoogle Scholar
  94. 94.
    Hawton K, Simkin S, Deeks J (2003) Co-proxamol and suicide: a study of national mortality statistics and local non-fatal self poisonings. Br Med J 326:1006–1008CrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2006

Authors and Affiliations

  1. 1.Anaesthetics LaboratorySt. Bartholomew’s HospitalLondonUK

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