Clinical Pharmacokinetics

, Volume 43, Issue 13, pp 879–923

Clinical Pharmacology of Tramadol

Review Article

Abstract

Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ. opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (−)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate.

Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87–95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%.

Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours.

The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O-and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites.

The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated.

Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.

References

  1. 1.
    Schenck EG, Arend I. The effect of tramadol in an open clinical trial [in German]. Arzneimittel Forschung 1978; 28(1a): 209–12PubMedGoogle Scholar
  2. 2.
    Radbruch L, Grond S, Lehmann KA. A risk-benefit assessment of tramadol in the management of pain. Drug Saf 1996; 15(1): 8–29PubMedGoogle Scholar
  3. 3.
    Keup W. Missbrauchsmuster bei Abhängigkeit von Alkohol, Medikamenten und Drogen: Frühwarnsystem-Daten für die Bundesrepublik Deutschland 1976–1990. Freiburg: Lambertus, 1993Google Scholar
  4. 4.
    Raffa RB, Friderichs E, Reimann 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): 275–85PubMedGoogle Scholar
  5. 5.
    Raffa RB, Friderichs E, Reimann W, et al. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993; 267(1): 331–40PubMedGoogle Scholar
  6. 6.
    Lintz W, Barth H, Becker R, et al. Pharmacokinetics of tramadol and bioavailability of enterai tramadol formulations. 2nd communication: drops with ethanol. Arzneimittel Forschung 1998; 48(5): 436–45PubMedGoogle Scholar
  7. 7.
    Lintz W, Becker R, Gerloff J, et al. Pharmacokinetics of tramadol and bioavailability of enterai tramadol formulations. 4th communication: drops (without ethanol). Arzneimittel Forschung 2000; 50(2): 99–108PubMedGoogle Scholar
  8. 8.
    Lintz W, Barth H, Osterloh G, et al. Bioavailability of enterai tramadol formulations. 1st communication: capsules. Arzneimittel Forschung 1986; 36(8): 1278–83PubMedGoogle Scholar
  9. 9.
    Stadler T. Eckdaten zur Pharmakokinetik der Retardtablette Tramai long 100. Aachen: Grünenthal GmbH, 1994Google Scholar
  10. 10.
    Raffa RB, Nayak RK, Liao S, et al. The mechanism (s) of action and pharmacokinetics of tramadol hydrochloride. Rev Con-temp Pharmacother 1995; 6: 485–97Google Scholar
  11. 11.
    Lintz W, Barth H, Osterloh G, et al. Pharmacokinetics of tramadol and bioavailability of enterai tramadol formulations. 3rd communication: suppositories. Arzneimittel Forschung 1998; 48(9): 889–99PubMedGoogle Scholar
  12. 12.
    Liao S, Hill JF, Nayak RK. Pharmacokinetics of tramadol following single and multiple oral doses in man [abstract]. Pharm Res 1992; 9 Suppl.: 308Google Scholar
  13. 13.
    Data on file, Grünenthal GmbHGoogle Scholar
  14. 14.
    Schulz HU, Raber M, Schurer M, et al. Pharmacokinetic properties of tramadol sustained release capsules. 1st communication: investigation of dose linearity. Arzneimittel Forschung 1999; 49(7): 582–7PubMedGoogle Scholar
  15. 15.
    Raber M, Schulz HU, Schurer M, et al. Pharmacokinetic properties of tramadol sustained release capsules. 2nd communication: investigation of relative bioavailability and food interaction. Arzneimittel Forschung 1999; 49(7): 588–93PubMedGoogle Scholar
  16. 16.
    Raber M, Schulz HU, Schurer M, et al. Pharmacokinetic properties of tramadol sustained release capsules. 3rd communication: investigation of relative bioavailability under steady state conditions. Arzneimittel Forschung 1999; 49(7): 594–8PubMedGoogle Scholar
  17. 17.
    Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after i.m. injection in comparison to i.V. infusion. Int J Clin Pharmacol Ther 1999; 37(4): 175–83PubMedGoogle Scholar
  18. 18.
    Chao CK, Yu LL, Su LL, et al. Bioequivalence study of tramadol by intramuscular administration in healthy volunteers. Arzneimittel Forschung 2000; 50(7): 636–40PubMedGoogle Scholar
  19. 19.
    Lintz W. Aktuelle pharmakokinetische Ergebnisse zu Tramai. Stolberg: Grünenthal GmbH, 1991Google Scholar
  20. 20.
    Lintz W. Overall summary on pharmacokinetics of tramadol in man. Aachen: Grünenthal GmbH, 1992Google Scholar
  21. 21.
    Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride. Pain Rev 1998; 5: 155–82Google Scholar
  22. 22.
    Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000; 60(1): 139–76PubMedGoogle Scholar
  23. 23.
    Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993; 46(2): 313–40PubMedGoogle Scholar
  24. 24.
    Liao S, Hill JF, Stubbs R. The effect of food on the bioavailability of tramadol [abstract]. Pharm Res 1992; 9 Suppl.: 308Google Scholar
  25. 25.
    Hopkins D, Shipton EA, Potgieter D, et al. Comparison of tramadol and morphine via subcutaneous PCA following major orthopaedic surgery. Can J Anaesth 1998; 45 (5 Pt 1): 435–42PubMedGoogle Scholar
  26. 26.
    Tramundin SL® product information. Limburg: Mundipharma GmbH, 1998Google Scholar
  27. 27.
    Malonne H, Fontaine J, Moes A. In vitro/in vivo characterization of a tramadol HC1 depot system composed of monoolein and water. Biol Pharm Bull 2000; 23(5): 627–31PubMedGoogle Scholar
  28. 28.
    Tao Q, Stone DJ, Borenstein MR, et al. Differential tramadol and O-desmethyl metabolite levels in brain vs plasma of mice and rats administered tramadol hydrochloride orally. J Clin Pharm Ther 2002; 27(2): 99–106PubMedGoogle Scholar
  29. 29.
    Husslein P, Kubista E, Egarter C. Obstetrical analgesia with tramadol: results of a prospective randomized comparative study with pethidine [in German]. Z Geburtshilfe Perinatol 1987; 191(6): 234–7PubMedGoogle Scholar
  30. 30.
    Lintz W, Erlacin S, Frankus E, et al. Biotransformation of tramadol in man and animal [in German]. Arzneimittel Forschung 1981; 31(11): 1932–43PubMedGoogle Scholar
  31. 31.
    Paar WD, Poche S, Gerloff J, et al. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997; 53(3–4): 235–9PubMedGoogle Scholar
  32. 32.
    Ogunleye DS. Investigation of racial variations in the metabolism of tramadol. Eur J Drug Metab Pharmacokinet 2001; 26(1–2): 95–8PubMedGoogle Scholar
  33. 33.
    Wu WN, McKown LA, Liao S. Metabolism of the analgesic drug Ultram® (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites. Xenobiotica 2002; 32(5): 411–25PubMedGoogle Scholar
  34. 34.
    Wu WN, McKown LA, Gauthier AD, et al. Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog. Xenobiotica 2001; 31(7): 423–41PubMedGoogle Scholar
  35. 35.
    Nobilis M, Kopecky J, Kvetina J, et al. High-performance liquid Chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma: application to a bioequivalence study in humans. J Chromatogr A 2002; 949(1–2): 11–22PubMedGoogle Scholar
  36. 36.
    Thurauf N, Fleischer WK, Liefhold J, et al. Dose dependent time course of the analgesic effect of a sustained-release preparation of tramadol on experimental phasic and tonic pain. Br J Clin Pharmacol 1996; 41(2): 115–23PubMedGoogle Scholar
  37. 37.
    Murthy BV, Pandya KS, Booker PD, et al. Pharmacokinetics of tramadol in children after i.V. or caudal epidural administration. Br J Anaesth 2000; 84(3): 346–9PubMedGoogle Scholar
  38. 38.
    Wu WN, McKown LA, Codd EE, et al. In vitro metabolism of the analgesic agent, tramadol-N-oxide, in mouse, rat, and human. Eur J Drug Metab Pharmacokinet 2002; 27(3): 193–7PubMedGoogle Scholar
  39. 39.
    Raffa RB, Haslego ML, Maryanoff CA, et al. Unexpected antinociceptive effect of the N-oxide (RWJ 38705) of tramadol hydrochloride. J Pharmacol Exp Ther 1996; 278(3): 1098–104PubMedGoogle Scholar
  40. 40.
    Paar WD, Frankus P, Dengler HJ. The metabolism of tramadol by human liver microsomes. Clin Invest 1992; 70(8): 708–10Google Scholar
  41. 41.
    Subrahmanyam V, Renwick AB, Walters DG, et al. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001; 29(8): 1146–55PubMedGoogle Scholar
  42. 42.
    Lledo P. Variations in drug metabolism due to genetic polymorphism: a review of the debrisoquinidine/sparteine type. Drug Invest 1993; 5: 19–34Google Scholar
  43. 43.
    Collart L, Luthy C, Dayer P. Multimodal analgesic effect of tramadol [abstract]. Clin Pharmacol Ther 1993; 53: 223Google Scholar
  44. 44.
    Poulsen L, Arendt-Nielsen L, Brosen K, et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60(6): 636–44PubMedGoogle Scholar
  45. 45.
    Abdel-Rahman SM, Leeder JS, Wilson JT, et al. Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol 2002; 42(1): 24–9PubMedGoogle Scholar
  46. 46.
    Gan SH, Ismail R, Wan Adnan WA, et al. Correlation of tramadol pharmacokinetics and CYP2D6*10 genotype in Malaysian subjects. J Pharm Biomed Anal 2002; 30(2): 189–95PubMedGoogle Scholar
  47. 47.
    Hamm S, von Unruh GE, Paar WD, et al. Isotope effects during metabolism of (±)-tramadol isoptomers by human liver microsomes. Istopenpraxis Environ Health Stud 1994; 30: 99–110Google Scholar
  48. 48.
    Liu HC, Zhang XJ, Yang YY, et al. Stereoselectivity in renal clearance of trans-tramadol and its active metabolite, trans-O-demethyltramadol. Acta Pharmacol Sin 2002; 23(1): 83–6PubMedGoogle Scholar
  49. 49.
    Liu HC, Wang N, Liu CS, et al. Distribution of enantiomers of trans-tramadol and trans-O-demethyltramadol in central nervous system of rats. Acta Pharmacol Sin 2001; 22(10): 871–5PubMedGoogle Scholar
  50. 50.
    Valle M, Garrido MJ, Pavon JM, et al. Pharmacokineticpharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (−)-O-desmethyltramadol, in rats. J Pharmacol Exp Ther 2000; 293(2): 646–53PubMedGoogle Scholar
  51. 51.
    Garrido MJ, Valle M, Campanero MA, et al. Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (−)-O-desmethyltramadol, in rats. J Pharmacol Exp Ther 2000; 295(1): 352–9PubMedGoogle Scholar
  52. 52.
    Campanero MA, Calahorra B, Valle M, et al. Enantiomeric separation of tramadol and its active metabolite in human plasma by chiral high-performance liquid chromatography: application to pharmacokinetic studies. Chirality 1999; 11(4): 272–9PubMedGoogle Scholar
  53. 53.
    Ceccato A, Vanderbist F, Pabst JY, et al. Enantiomeric determination of tramadol and its main metabolite O-desmethyl-tramadol in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 2000; 748(1): 65–76PubMedGoogle Scholar
  54. 54.
    Liu HC, Liu TJ, Yang YY, et al. Pharmacokinetics of enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in human subjects. Acta Pharmacol Sin 2001; 22(1): 91–6PubMedGoogle Scholar
  55. 55.
    Rudaz S, Veuthey JL, Desiderio C, et al. Simultaneous stereoselective analysis by capillary electrophoresis of tramadol enantiomers and their main phase I metabolites in urine. J Chromatogr A 1999; 846(1–2): 227–37PubMedGoogle Scholar
  56. 56.
    Elsing B, Blaschke G. Achiral and chiral high-performance liquid Chromatographic determination of tramadol and its major metabolites in urine after oral administration of racemic tramadol. J Chromatogr 1993; 612(2): 223–30PubMedGoogle Scholar
  57. 57.
    Kurth B, Blaschke G. Achiral and chiral determination of tramadol and its metabolites in urine by capillary electrophoresis. Electrophoresis 1999; 20(3): 555–63PubMedGoogle Scholar
  58. 58.
    Soetebeer UB, Schierenberg MO, Schulz H, et al. Direct chiral assay of tramadol and detection of the phase II metabolite O-demethyl tramadol glucuronide in human urine using capillary electrophoresis with laser-induced native fluorescence detection. J Chromatogr B Biomed Sci Appl 2001; 765(1): 3–13PubMedGoogle Scholar
  59. 59.
    Overbeck P, Blaschke G. Direct determination of tramadol glucuronides in human urine by high-performance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl 1999; 732(1): 185–92PubMedGoogle Scholar
  60. 60.
    Frink MC, Hennies HH, Englberger W, et al. Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittel Forschung 1996; 46(11): 1029–36PubMedGoogle Scholar
  61. 61.
    Hummel T, Roscher S, Pauli E, et al. Assessment of analgesia in man: tramadol controlled release formula vs tramadol standard formulation. Eur J Clin Pharmacol 1996; 51(1): 31–8PubMedGoogle Scholar
  62. 62.
    Grond S, Meuser T, Uragg H, et al. Serum concentrations of tramadol enantiomers during patient-controlled analgesia. Br J Clin Pharmacol 1999; 48(2): 254–7PubMedGoogle Scholar
  63. 63.
    Hackl W, Fitzal S, Lackner F, et al. Comparison of fentanyl and tramadol in pain therapy with an on-demand analgesia computer in the early postoperative phase [in German]. Anaesthesist 1986; 35(11): 665–71PubMedGoogle Scholar
  64. 64.
    Lehmann KA, Kratzenberg U, Schroeder-Bark B, et al. Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. Clin J Pain 1990; 6(3): 212–20PubMedGoogle Scholar
  65. 65.
    Lehmann KA. Tramadol for the management of acute pain. Drugs 1994; 47 Suppl. 1: 19–32PubMedGoogle Scholar
  66. 66.
    Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 1999; 37(1): 17–40PubMedGoogle Scholar
  67. 67.
    Izzedine H, Launay-Vacher V, Abbara C, et al. Pharmacokinetics of tramadol in a hemodialysis patient. Nephron 2002; 92(3): 755–6PubMedGoogle Scholar
  68. 68.
    Boeijinga JK, van Meegen E, van den Ende R, et al. Lack of interaction between tramadol and coumarins. J Clin Pharmacol 1998; 38(10): 966–70PubMedGoogle Scholar
  69. 69.
    Raffa RB, Friderichs E. The basic science aspect of tramadol hydrochloride. Pain Rev 1996; 3: 249–71Google Scholar
  70. 70.
    Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittel Forschung 1988; 38(7): 877–80PubMedGoogle Scholar
  71. 71.
    Kögel B, Englberger W, Hennies HH, et al. Involvement of metabolites in the analgesic action of tramadol [abstract]. 9th World Congress of Pain; 1999 Aug 22–27; Vienna, 523Google Scholar
  72. 72.
    Desmeules JA, Piguet V, Collart L, et al. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996; 41(1): 7–12PubMedGoogle Scholar
  73. 73.
    Gillen C, Haurand M, Kobelt DJ, et al. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000; 362(2): 116–21PubMedGoogle Scholar
  74. 74.
    Frankus E, Friderichs E, Kim SM, et al. On separation of isomeres, structural elucidation and pharmacological characterization of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol [in German]. Arzneimittel Forschung 1978; 28(1a): 114–21PubMedGoogle Scholar
  75. 75.
    Driessen B, Reimann W. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxy-tryptamine in the rat brain in vitro. Br J Pharmacol 1992; 105(1): 147–51PubMedGoogle Scholar
  76. 76.
    Bamigbade TA, Davidson C, Langford RM, et al. 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 1997; 79(3): 352–6PubMedGoogle Scholar
  77. 77.
    Reimann W, Schneider F. Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine. Eur J Pharmacol 1998; 349(2–3): 199–203PubMedGoogle Scholar
  78. 78.
    Gobbi M, Mennini T. Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser. Eur J Pharmacol 1999; 370(1): 23–6PubMedGoogle Scholar
  79. 79.
    Oliva P, Aurilio C, Massimo F, et al. The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 2002; 445(3): 179–85PubMedGoogle Scholar
  80. 80.
    Reimann W, Hennies HH. Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol. Biochem Pharmacol 1994; 47(12): 2289–93PubMedGoogle Scholar
  81. 81.
    Sagata K, Minami K, Yanagihara N, et al. Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg 2002; 94(4): 901–6PubMedGoogle Scholar
  82. 82.
    Halfpenny DM, Callado LF, Hopwood SE, et al. Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry. Br J Anaesth 1999; 83(6): 909–15PubMedGoogle Scholar
  83. 83.
    Driessen B, Reimann W, Giertz H. Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro. Br J Pharmacol 1993; 108(3): 806–11PubMedGoogle Scholar
  84. 84.
    Collart L, Luthy C, Favario-Constantin C, et al. Duality of the analgesic effect of tramadol in humans [in German]. Schweiz Med Wochenschr 1993; 123(47): 2241–3PubMedGoogle Scholar
  85. 85.
    Parth P, Madler C, Morawetz RF. Characterization of the effect of analgesics on the assessment of experimental pain in man. Pethidine and tramadol in a double-blind comparison [in German]. Anaesthesist 1984; 33(5): 235–9PubMedGoogle Scholar
  86. 86.
    Collart L, Luthy C, Dayer P. Partial inhibition of tramadol antinociceptive effect by naloxone in man [abstract]. Br J Clin Pharmacol 1993; 35: 73PGoogle Scholar
  87. 87.
    Arcioni R, della Rocca M, Romano S, et al. Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans. Anesth Analg 2002; 94(6): 1553–7PubMedGoogle Scholar
  88. 88.
    De Witte JL, Schoenmaekers B, Sessler DI, et al. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001; 92(5): 1319–21PubMedGoogle Scholar
  89. 89.
    Grond S, Meuser T, Zech D, et al. Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia. Pain 1995; 62(3): 313–20PubMedGoogle Scholar
  90. 90.
    Wiebalck A, Zenz M, Tryba M, et al. Are tramadol enantiomers for postoperative pain therapy better suited than the racemate: a randomized, placebo- and morphine-controlled double blind study [in German]. Anaesthesist 1998; 47(5): 387–94PubMedGoogle Scholar
  91. 91.
    Violand C, Desmeules J, Piguet V, et al. The antinociceptive effects of tramadol and its enantiomers [abstract]. Schweiz Med Wochenschr 1999; 129 (13 Suppl.): 32SGoogle Scholar
  92. 92.
    Sunshine A. New clinical experience with tramadol. Drugs 1994; 47 Suppl. 1: 8–18PubMedGoogle Scholar
  93. 93.
    Nieuwenhuijs D, Bruce J, Drummond GB, et al. Influence of oral tramadol on the dynamic ventilatory response to carbon dioxide in healthy volunteers. Br J Anaesth 2001; 87(6): 860–5PubMedGoogle Scholar
  94. 94.
    Warren PM, Taylor JH, Nicholson KE, et al. Influence of tramadol on the ventilatory response to hypoxia in humans. Br J Anaesth 2000; 85(2): 211–6PubMedGoogle Scholar
  95. 95.
    Mildh LH, Leino KA, Kirvela OA. Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and hemodynamics. J Clin Anesth 1999; 11(4): 310–6PubMedGoogle Scholar
  96. 96.
    Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth 1997; 9(7): 582–5PubMedGoogle Scholar
  97. 97.
    Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998; 15(1): 64–8PubMedGoogle Scholar
  98. 98.
    Bosenberg AT, Ratcliffe S. The respiratory effects of tramadol in children under halothane anaesthesia. Anaesthesia 1998; 53(10): 960–4PubMedGoogle Scholar
  99. 99.
    Barth H, Giertz H, Schmal A, et al. Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents Actions 1987; 20(3–4): 310–3PubMedGoogle Scholar
  100. 100.
    Muller H, Stoyanov M, Brahler A, et al. Hemodynamic and respiratory effects of tramadol during nitrous oxide-oxygen artificial respiration and in the postoperative period [in German]. Anaesthesist 1982; 31(11): 604–10PubMedGoogle Scholar
  101. 101.
    Takacs AR. Ancillary approaches to toxicokinetic evaluations. Toxicol Pathol 1995; 23(2): 179–86PubMedGoogle Scholar
  102. 102.
    Ellmauer S, Dick W, Otto S, et al. Different opioids in patients at cardiovascular risk: comparison of central and peripheral hemodynamic adverse effects [in German]. Anaesthesist 1994; 43(11): 743–9PubMedGoogle Scholar
  103. 103.
    Rettig G, Kropp J. Analgesic effect of tramadol in acute myocardial infarct [in German]. Ther Ggw 1980; 119(6): 705–7PubMedGoogle Scholar
  104. 104.
    Murphy DB, Sutton A, Prescott LF, et al. A comparison of the effects of tramadol and morphine on gastric emptying in man. Anaesthesia 1997; 52(12): 1224–9PubMedGoogle Scholar
  105. 105.
    Crighton IM, Martin PH, Hobbs GJ, et al. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesth Analg 1998; 87(2): 445–9PubMedGoogle Scholar
  106. 106.
    Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol 1997; 43(1): 71–5PubMedGoogle Scholar
  107. 107.
    Wilder-Smith CH, Hill L, Osier W, et al. Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Dig Dis Sci 1999; 44(6): 1107–16PubMedGoogle Scholar
  108. 108.
    Wilder-Smith CH, Hill L, Wilkins J, et al. Effects of morphine and tramadol on somatic and visceral sensory function and gastrointestinal motility after abdominal surgery. Anesthesiology 1999; 91(3): 639–47PubMedGoogle Scholar
  109. 109.
    Staritz M, Poralla T, Manns M, et al. Effect of modern analgesic drugs (tramadol, pentazocine, and buprenorphine) on the bile duct sphincter in man. Gut 1986; 27(5): 567–9PubMedGoogle Scholar
  110. 110.
    Tsai YC, Won SJ. Effects of tramadol on T lymphocyte proliferation and natural killer cell activity in rats with sciatic constriction injury. Pain 2001; 92(1–2): 63–9PubMedGoogle Scholar
  111. 111.
    Gaspani L, Bianchi M, Limiroli E, et al. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J Neuroimmunol 2002; 129(1–2): 18–24PubMedGoogle Scholar
  112. 112.
    Sacerdote P, Bianchi M, Gaspani L, et al. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 2000; 90(6): 1411–4PubMedGoogle Scholar
  113. 113.
    Savoia G, Loreto M, Scibelli G. Systemic review of trials on the use of tramadol in the treatment of acute and chronic pain [in Italian]. Minerva Anestesiol 2000; 66(10): 713–31PubMedGoogle Scholar
  114. 114.
    Bamigbade TA, Langford RM, Blower AL. Pain control in day surgery: tramadol vs standard analgesia. Br J Anaesth 1998; 80: 558–9Google Scholar
  115. 115.
    Crighton IM, Hobbs GJ, Wrench IJ. Analgesia after day case laparoscopic sterilisation: a comparison of tramadol with paracetamol/dextropropoxyphene and paracetamol/codeine combinations. Anaesthesia 1997; 52(7): 649–52PubMedGoogle Scholar
  116. 116.
    Kupers R, Callebaut V, Debois V, et al. Efficacy and safety of oral tramadol and pentazocine for postoperative pain following prolapsed intervertebral disc repair. Acta Anaesthesiol Belg 1995; 46(1): 31–7PubMedGoogle Scholar
  117. 117.
    Peters AA, Witte EH, Damen AC, et al. Pain relief during and following outpatient curettage and hysterosalpingography: a double blind study to compare the efficacy and safety of tramadol versus naproxen. Cobra Research Group. Eur J Obstet Gynecol Reprod Biol 1996; 66(1): 51–6PubMedGoogle Scholar
  118. 118.
    Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effect of 50 and 100mg oral tramadol after orthopaedic surgery: a randomized, double-blind, placebo and standard active drug comparison. Pain 1995; 62(1): 111–8PubMedGoogle Scholar
  119. 119.
    Sunshine A, Olson NZ, Zighelboim I, et al. Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clin Pharmacol Ther 1992; 51(6): 740–6PubMedGoogle Scholar
  120. 120.
    Alon E, Schulthess G, Axhausen C, et al. A double-blind comparison of tramadol and buprenorphine in the control of postoperative pain [in German]. Anaesthesist 1981; 30(12): 623–6PubMedGoogle Scholar
  121. 121.
    Colletti V, Carner M, Vincenzi A. Intramuscular tramadol versus keterolac in the treatment of pain following nasal surgery: a controlled multicenter trial. Curr Ther Res Clin Exp 1998; 59: 608–18Google Scholar
  122. 122.
    de La Pena M, Togores B, Bosch M, et al. Recovery of lung function after laparoscopic cholecystectomy: the role of postoperative pain. Arch Bronconeumol 2002; 38(2): 72–6Google Scholar
  123. 123.
    Fassolt A. The analgesic effectiveness of Tramai (tramadol) 100mg for postoperative wound pain [in German]. Schweiz Rundsch Med Prax 1981; 70(10): 435–40PubMedGoogle Scholar
  124. 124.
    Gritti G, Verri M, Launo C, et al. Multicenter trial comparing tramadol and morphine for pain after abdominal surgery. Drugs Exp Clin Res 1998; 24(1): 9–16PubMedGoogle Scholar
  125. 125.
    Jeffrey HM, Charlten P, Mellor DJ, et al. Analgesia after intracranial surgery: a double-blind, prospective comparison of codeine and tramadol. Br J Anaesth 1999; 83(2): 245–9PubMedGoogle Scholar
  126. 126.
    Lanzetta A, Vizzardi M, Letizia G. Intramuscular tramadol versus keterolac in patients with orthopaedic and traumatologic postoperative pain: a comparative multicenter trial. Curr Ther Res Clin Exp 1998; 59: 39–47Google Scholar
  127. 127.
    Magrini M, Rivolta G, Bolis C, et al. Analgesic activity of tramadol and pentazocine in postoperative pain. Int J Clin Pharmacol Res 1998; 18(2): 87–92PubMedGoogle Scholar
  128. 128.
    Bloch MB, Dyer RA, Heijke SA, et al. Tramadol infusion for postthoracotomy pain relief: a placebo-controlled comparison with epidural morphine. Anesth Analg 2002; 94(3): 523–8PubMedGoogle Scholar
  129. 129.
    Dejonckheere M, Desjeux L, Deneu S, et al. Intravenous tramadol compared to propacetamol for postoperative analgesia following thyroidectomy. Acta Anaesthesiol Belg 2001; 52(1): 29–33PubMedGoogle Scholar
  130. 130.
    Driessen A, Grogass B, Glocke M. Vergleichende Untersuchungen zur postoperativen Schmerzbehandlung nach vaginalen Hysterektomien. Anästhesth Intensivmed 1984; 25: 26–9Google Scholar
  131. 131.
    Houmes RJ, Voets MA, Verkaaik A, et al. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg 1992; 74(4): 510–4PubMedGoogle Scholar
  132. 132.
    Manji M, Rigg C, Jones P. Tramadol for postoperative analgesia in coronary artery bypass graft surgery [abstract]. Br J Anaesth 1997; 78 Suppl. 2: 44Google Scholar
  133. 133.
    Olle FG, Opisso JL, Oferil RF, et al. Ketorolac versus tramadol: comparative study of analgesic efficacy in the postoperative pain in abdominal hysterectomy. Rev Esp Anestesiol Reanim 2000; 47(4): 162–7Google Scholar
  134. 134.
    Putland AJ, McCluskey A. The analgesic efficacy of tramadol versus ketorolac in day-case laparoscopic sterilisation. Anaesthesia 1999; 54(4): 382–5PubMedGoogle Scholar
  135. 135.
    Ranucci M, Cazzaniga A, Soro G, et al. Postoperative analgesia for early extubation after cardiac surgery: a prospective, randomized trial. Minerva Anestesiol 1999; 65(12): 859–65PubMedGoogle Scholar
  136. 136.
    Sellin M, Louvard V, Sicsic JC. Postoperative pain: tramadol versus morphine after cardiac surgery [abstract]. Br J Anaesth 1998; 80 Suppl. 2: 41Google Scholar
  137. 137.
    Stankov G, Schmieder G, Lechner FJ. Observer-blind multicentre study with metamizole versus tramadol in postoperative pain. Eur J Pain 1995; 16: 56–63Google Scholar
  138. 138.
    Striebel HW, Hackenberger J. A comparison of a tramadol/metamizole infusion with the combination tramadol infusion plus ibuprofen suppositories for postoperative pain management following hysterectomy [in German]. Anaesthesist 1992; 41(6): 354–60PubMedGoogle Scholar
  139. 139.
    Torres LM, Rodriguez MJ, Montera A, et al. Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: a randomized, double-blind, multicenter study. Reg Anesth Pain Med 2001; 26(2): 118–24PubMedGoogle Scholar
  140. 140.
    Tryba M, Zenz M. Wirksamkeit und Nebenwirkungen von Opioiden und alpha2-Adrenozeptor-agonisten in der Therapie postoperativer Schmerzen. Schmerz 1992; 6: 182–91PubMedGoogle Scholar
  141. 141.
    Vickers MD, Paravicini D. Comparison of tramadol with morphine for post-operative pain following abdominal surgery. Eur J Anaesthesiol 1995; 12(3): 265–71PubMedGoogle Scholar
  142. 142.
    Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain 1997; 69(3): 287–94PubMedGoogle Scholar
  143. 143.
    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; 23(2): 121–30PubMedGoogle Scholar
  144. 144.
    Roelofse JA, Payne KA. Oral tramadol: analgesic efficacy in children following multiple dental extractions. Eur J Anaesthesiol 1999; 16(7): 441–7PubMedGoogle Scholar
  145. 145.
    Finkel JC, Rose JB, Schmitz ML, et al. An evaluation of the efficacy and tolerability of oral tramadol hydrochloride tablets for the treatment of postsurgical pain in children. Anesth Analg 2002; 94(6): 1469–73PubMedGoogle Scholar
  146. 146.
    Courtney MJ, Cabraal D. Tramadol vs diclofenac for posttonsillectomy analgesia. Arch Otolaryngol Head Neck Surg 2001; 127(4): 385–8PubMedGoogle Scholar
  147. 147.
    Pluim MA, Wegener JT, Rupreht J, et al. Tramadol suppositories are less suitable for post-operative pain relief than rectal acetaminophen/codeine. Eur J Anaesthesiol 1999; 16(7): 473–8PubMedGoogle Scholar
  148. 148.
    Hartjen K, Fischer MV, Mewes R, et al. Preventive pain therapy: preventive tramadol infusion versus bolus application in the early postoperative phase [in German]. Anaesthesist 1996; 45(6): 538–44PubMedGoogle Scholar
  149. 149.
    Rud U, Fischer MV, Mewes R, et al. Postoperative analgesia with tramadol: continuous infusion versus repetitive bolus administration [in German]. Anaesthesist 1994; 43(5): 316–21PubMedGoogle Scholar
  150. 150.
    Webb AR, Leong S, Myles PS, et al. The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial. Anesth Analg 2002; 95(6): 1713–8PubMedGoogle Scholar
  151. 151.
    Griessinger N, Rosch W, Schott G, et al. Tramadol infusion for pain therapy following bladder exstrophy surgery in pediatric wards [in German]. Urologe A 1997; 36(6): 552–6PubMedGoogle Scholar
  152. 152.
    Pieri M, Meacci L, Santini L, et al. Control of acute pain after major abdominal surgery in 585 patients given tramadol and ketorolac by intravenous infusion. Drugs Exp Clin Res 2002; 28(2–3): 113–8PubMedGoogle Scholar
  153. 153.
    Bhatnagar S, Saxena A, Kannan TR, et al. Tramadol for postoperative shivering: a double-blind comparison with pethidine. Anaesth Intensive Care 2001; 29(2): 149–54PubMedGoogle Scholar
  154. 154.
    De Witte J, Deloof T, de Veylder J, et al. Tramadol in the treatment of postanesthetic shivering. Acta Anaesthesiol Scand 1997; 41(4): 506–10PubMedGoogle Scholar
  155. 155.
    Mathews S, Al Mulla A, Varghese PK, et al. Postanaesthetic shivering: a new look at tramadol. Anaesthesia 2002; 57(4): 394–8PubMedGoogle Scholar
  156. 156.
    Trekova N, Bunatian A, Zolicheva N. Tramadol hydrochloride in the management of postoperative shivering: a double-blind trial with placebo [abstract 264]. 9th World Congress on Pain; 1999 Aug 22–27; Vienna, 337Google Scholar
  157. 157.
    Chan AM, Ng KF, Tong EW, et al. Control of shivering under regional anesthesia in obstetric patients with tramadol. Can J Anaesth 1999; 46(3): 253–8PubMedGoogle Scholar
  158. 158.
    Tsai YC, Chu KS. A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients. Anesth Analg 2001; 93(5): 1288–92PubMedGoogle Scholar
  159. 159.
    Lehmann KA, Horrichs G, Hoeckle W. The significance of tramadol as an intraoperative analgesic: a randomized doubleblind study in comparison with placebo [in German]. Anaesthesist 1985; 34(1): 11–9PubMedGoogle Scholar
  160. 160.
    Naguib M, Seraj M, Attia M, et al. Perioperative antinociceptive effects of tramadol: a prospective, randomized, double-blind comparison with morphine. Can J Anaesth 1998; 45(12): 1168–75PubMedGoogle Scholar
  161. 161.
    Naguib M, Attia M, Samarkandi AH. Wound closure tramadol administration has a short-lived analgesic effect. Can J Anaesth 2000; 47(8): 815–8PubMedGoogle Scholar
  162. 162.
    De Witte J, Rietman GW, Vandenbroucke G, et al. Postoperative effects of tramadol administered at wound closure. Eur J Anaesthesiol 1998; 15(2): 190–5PubMedGoogle Scholar
  163. 163.
    Coetzee JF, van Loggerenberg H. Tramadol or morphine administered during operation: a study of immediate postoperative effects after abdominal hysterectomy. Br J Anaesth 1998; 81(5): 737–41PubMedGoogle Scholar
  164. 164.
    James MF, Heijke SA, Gordon PC. Intravenous tramadol versus epidural morphine for postthoracotomy pain relief: a placebocontrolled double-blind trial. Anesth Analg 1996; 83(1): 87–91PubMedGoogle Scholar
  165. 165.
    Viitanen H, Annila P. Analgesic efficacy of tramadol 2mg kg−1 for paediatric day-case adenoidectomy. Br J Anaesth 2001; 86(4): 572–5PubMedGoogle Scholar
  166. 166.
    Pendeville PE, Von Montigny S, Dort JP, et al. Double-blind randomized study of tramadol vs paracetamol in analgesia after day-case tonsillectomy in children. Eur J Anaesthesiol 2000; 17(9): 576–82PubMedGoogle Scholar
  167. 167.
    Ozkose Z, Akcabay M, Kemaloglu YK, et al. Relief of posttonsillectomy pain with low-dose tramadol given at induction of anesthesia in children. Int J Pediatr Otorhinolaryngol 2000; 53(3): 207–14PubMedGoogle Scholar
  168. 168.
    Chiaretti A, Viola L, Pietrini D, et al. Preemptive analgesia with tramadol and fentanyl in pediatric neurosurgery. Childs Nerv Syst 2000; 16(2): 93–9PubMedGoogle Scholar
  169. 169.
    van den Berg AA, Montoya-Pelaez LF, Halliday EM, et al. Analgesia for adenotonsillectomy in children and young adults: a comparison of tramadol, pethidine and nalbuphine. Eur J Anaesthesiol 1999; 16(3): 186–94PubMedGoogle Scholar
  170. 170.
    Wong WH, Cheong KF. Role of tramadol in reducing pain on propofol injection. Singapore Med J 2001; 42(5): 193–5PubMedGoogle Scholar
  171. 171.
    Memis D, Turan A, Karamanlioglu B, et al. The prevention of propofol injection pain by tramadol or ondansetron. Eur J Anaesthesiol 2002; 19(1): 47–51PubMedGoogle Scholar
  172. 172.
    Tan SM, Pay LL, Chan ST. Intravenous regional anaesthesia using lignocaine and tramadol. Ann Acad Med Singapore 2001; 30(5): 516–9PubMedGoogle Scholar
  173. 173.
    Acalovschi I, Cristea T, Margarit S, et al. Tramadol added to lidocaine for intravenous regional anesthesia. Anesth Analg 2001; 92(1): 209–14PubMedGoogle Scholar
  174. 174.
    Choyce A, Peng P. A systematic review of adjuncts for intravenous regional anesthesia for surgical procedures. Can J Anaesth 2002; 49(1): 32–45PubMedGoogle Scholar
  175. 175.
    Langlois G, Estebe JP, Gentili ME, et al. The addition of tramadol to lidocaine does not reduce tourniquet and postoperative pain during iv regional anesthesia. Can J Anaesth 2002; 49(2): 165–8PubMedGoogle Scholar
  176. 176.
    Lehmann KA. New developments in patient-controlled postoperative analgesia. Ann Med 1995; 27: 271–82PubMedGoogle Scholar
  177. 177.
    Jellinek H, Haumer H, Grubhofer G, et al. Tramadol in postoperative pain therapy: patient-controlled analgesia versus continuous infusion [in German]. Anaesthesist 1990; 39(10): 513–20PubMedGoogle Scholar
  178. 178.
    Stamer UM, Maier C, Grond S, et al. Tramadol in the management of post-operative pain: a double-blind, placebo- and active drug-controlled study. Eur J Anaesthesiol 1997; 14(6): 646–54PubMedGoogle Scholar
  179. 179.
    Ng KF, Tsui SL, Yang JC, et al. Increased nausea and dizziness when using tramadol for post-operative patient-controlled analgesia (PCA) compared with morphine after intraoperative loading with morphine. Eur J Anaesthesiol 1998; 15(5): 565–70PubMedGoogle Scholar
  180. 180.
    Pang WW, Mok MS, Lin CH, et al. Comparison of patient-controlled analgesia (PCA) with tramadol or morphine. Can J Anaesth 1999; 46(11): 1030–5PubMedGoogle Scholar
  181. 181.
    Silvasti M, Svartling N, Pitkanen M, et al. Comparison of intravenous patient-controlled analgesia with tramadol versus morphine after microvascular breast reconstruction. Eur J Anaesthesiol 2000; 17(7): 448–55PubMedGoogle Scholar
  182. 182.
    Stamer UM, Grond S, Maier C. Responders and non-responders to post-operative pain treatment: the loading dose predicts analgesic needs. Eur J Anaesthesiol 1999; 16(2): 103–10PubMedGoogle Scholar
  183. 183.
    Alon E, Atanassoff PG, Biro P. Intravenous postoperative pain management using nalbuphine and tramadol: a combination of continuous infusion and patient-controlled administration [in German]. Anaesthesist 1992; 41(2): 83–7PubMedGoogle Scholar
  184. 184.
    Lehmann KA, Jung C, Hoeckle W. Tramadol und Pethidin zur postoperativen Schmerztherapie: eine Doppelblindstudie unter den Bedingungen der intravenösen on-demand Analgesie. Eur J Pain 1985; 6: 88–100Google Scholar
  185. 185.
    Likar R, Jost R, Mathiaschitz K. Postoperative patient-controlled analgesia using a low-tech PCA system. Int J Acute Pain Manage 1999; 2: 17–26Google Scholar
  186. 186.
    Migliorini F, Tropea F, Perciaccante L. Tramadol in PCA plus propacetamol is a good choice after orthopaedic surgery [abstract]. Br J Anaesth 1999; 82 Suppl. 1: 190Google Scholar
  187. 187.
    Montes A, Warner W, Puig MM. Use of intravenous patient-controlled analgesia for the documentation of synergy between tramadol and metamizol. Br J Anaesth 2000; 85(2): 217–23PubMedGoogle Scholar
  188. 188.
    Pang W, Huang S, Tung CC, et al. Patient-controlled analgesia with tramadol versus tramadol plus lysine acetyl salicylate. Anesth Analg 2000; 91(5): 1226–9PubMedGoogle Scholar
  189. 189.
    Rodriguez MJ, De La Torre MR, Perez-Iraola P. Comparative study of tramadol versus NSAIDs as intravenous continuous infusion for managing postoperative pain. Curr Ther Res 1993; 54: 375–83Google Scholar
  190. 190.
    Silvasti M, Tarkkila P, Tuominen M, et al. Efficacy and side effects of tramadol versus oxycodone for patient-controlled analgesia after maxillofacial surgery. Eur J Anaesthesiol 1999; 16(12): 834–9PubMedGoogle Scholar
  191. 191.
    Vickers MD, O’Flaherty D, Szekely SM, et al. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia 1992; 47(4): 291–6PubMedGoogle Scholar
  192. 192.
    Pang WW, Mok MS, Huang S, et al. Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Can J Anaesth 2000; 47(10): 968–73PubMedGoogle Scholar
  193. 193.
    Ng KF, Tsui SL, Yang JC, et al. Comparison of tramadol and tramadol/droperidol mixture for patient-controlled analgesia. Can J Anaesth 1997; 44(8): 810–5PubMedGoogle Scholar
  194. 194.
    Siddik-Sayyid S, Aouad-Maroun M, Sleiman D, et al. Epidural tramadol for postoperative pain after Cesarean section. Can J Anaesth 1999; 46(8): 731–5PubMedGoogle Scholar
  195. 195.
    Grace D, Fee JP. Ineffective analgesia after extradural tramadol hydrochloride in patients undergoing total knee replacement. Anaesthesia 1995; 50(6): 555–8PubMedGoogle Scholar
  196. 196.
    Delilkan AE, Vijayan R. Epidural tramadol for postoperative pain relief. Anaesthesia 1993; 48(4): 328–31PubMedGoogle Scholar
  197. 197.
    Baraka A, Jabbour S, Ghabash M, et al. A comparison of epidural tramadol and epidural morphine for postoperative analgesia. Can J Anaesth 1993; 40(4): 308–13PubMedGoogle Scholar
  198. 198.
    Pan AK, Mukherjee P, Rudra A. Role of epidural tramadol hydrochloride on postoperative pain relief in caesarean section delivery. J Indian Med Assoc 1997; 95(4): 105–6PubMedGoogle Scholar
  199. 199.
    Ozcengiz D, Gunduz M, Ozbek H, et al. Comparison of caudal morphine and tramadol for postoperative pain control in children undergoing inguinal herniorrhaphy. Paediatr Anaesth 2001; 11(4): 459–64PubMedGoogle Scholar
  200. 200.
    Senel AC, Akyol A, Dohman D, et al. Caudal bupivacainetramadol combination for postoperative analgesia in pediatric herniorrhaphy. Acta Anaesthesiol Scand 2001; 45(6): 786–9PubMedGoogle Scholar
  201. 201.
    Gunduz M, Ozcengiz D, Ozbek H, et al. A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children. Paediatr Anaesth 2001; 11(3): 323–6PubMedGoogle Scholar
  202. 202.
    Batra YK, Prasad MK, Arya VK, et al. Comparison of caudal tramadol vs bupivacaine for post-operative analgesia in children undergoing hypospadias surgery. Int J Clin Pharmacol Ther 1999; 37(5): 238–42PubMedGoogle Scholar
  203. 203.
    Presser DP, Davis A, Booker PD, et al. Caudal tramadol for postoperative analgesia in pediatric hypospadias surgery. Br J Anaesth 1997; 79(3): 293–6Google Scholar
  204. 204.
    Likar R, Mathiaschitz K, Burtscher M. Randomized, double-blind, comparative study of morphine and tramadol administered intra-articularly for postoperative analgesia following arthroscopic surgery. Clin Drug Invest 1995; 10(1): 17–21Google Scholar
  205. 205.
    Kapral S, Gollmann G, Waltl B, et al. Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg 1999; 88(4): 853–6PubMedGoogle Scholar
  206. 206.
    Sommer F. Klinische Erfahrung mit dem Analgetikum Tramadol-HCl Erfahrungsbericht aus einer orthopädischen Praxis. Extracta Med Pract 1981; 2: 826–31Google Scholar
  207. 207.
    Berghold F, Aufmesser H, Aufmesser W. Erstversorgung von Wintersportverletzungen: analgetische Wirksamkeit und Verträglichkeit von Tramadol. Therapiewoche Österreich 1991; 6: 173–84Google Scholar
  208. 208.
    Ward ME, Radburn J, Morant S. Evaluation of intravenous tramadol for use in the prehospital situation by ambulance paramedics. Prehospital Disaster Med 1997; 12(2): 158–62PubMedGoogle Scholar
  209. 209.
    Vergnion M, Degesves S, Garcet L, et al. Tramadol, an alternative to morphine for treating posttraumatic pain in the prehospital situation. Anesth Analg 2001; 92(6): 1543–6PubMedGoogle Scholar
  210. 210.
    Hoogewijs J, Diltoer MW, Hubloue I, et al. A prospective, open, single blind, randomized study comparing four analgesics in the treatment of peripheral injury in the emergency department. Eur J Emerg Med 2000; 7(2): 119–23PubMedGoogle Scholar
  211. 211.
    Mahadevan M, Graff L. Prospective randomized study of analgesic use for ED patients with right lower quadrant abdominal pain. Am J Emerg Med 2000; 18(7): 753–6PubMedGoogle Scholar
  212. 212.
    Eray O, Cete Y, Oktay C, et al. Intravenous single-dose tramadol versus meperidine for pain relief in renal colic. Eur J Anaesthesiol 2002; 19(5): 368–70PubMedGoogle Scholar
  213. 213.
    Nicolas Torralba JA, Rigabert Montiel M, Banon Perez V, et al. Intramuscular ketorolac compared to subcutaneous tramadol in the initial emergency treatment of renal colic [in Spanish]. Arch Esp Urol 1999; 52(5): 435–7PubMedGoogle Scholar
  214. 214.
    Stankov G, Schmieder G, Zerle G, et al. Double-blind study with dipyrone versus tramadol and butylscopolamine in acute renal colic pain. World J Urol 1994; 12(3): 155–61PubMedGoogle Scholar
  215. 215.
    Schmieder G, Stankov G, Zerle G, et al. Observer-blind study with metamizole versus tramadol and butylscopolamine in acute biliary colic pain. Arzneimittel Forschung 1993; 43(11): 1216–21PubMedGoogle Scholar
  216. 216.
    Primus G, Pummer K, Vucsina F, et al. Tramadol versus metimazole in alleviating pain in ureteral colic [in German]. Urologe A 1989; 28(2): 103–5PubMedGoogle Scholar
  217. 217.
    Elbourne D, Wiseman RA. Types of intra-muscular opioids for maternal pain relief in labour. Cochrane Database Syst Rev 2000; (2): CD001237PubMedGoogle Scholar
  218. 218.
    Viegas OA, Khaw B, Ratnam SS. Tramadol in labour pain in primiparous patients: a prospective comparative clinical trial. Eur J Obstet Gynecol Reprod Biol 1993; 49(3): 131–5PubMedGoogle Scholar
  219. 219.
    Kainz C, Joura E, Obwegeser R, et al. Effectiveness and tolerance of tramadol with or without an antiemetic and pethidine in obstetric analgesia [in German]. Z Geburtshilfe Perinatal 1992; 196(2): 78–82Google Scholar
  220. 220.
    Fieni S, Angeri F, Kaihura CT, et al. Evaluation of the peripartum effects of 2 analgesics: meperidine and tramadol, used in labor. Acta Biomed Ateneo Parmense 2000; 71 Suppl. 1: 397–400PubMedGoogle Scholar
  221. 221.
    Li E, Weng L. Influence of dihydroetorphine hydrochloride and tramadol on labor pain and umbilical blood gas. Zhonghua Fu Chan Ke Za Zhi 1995; 30(6): 345–8PubMedGoogle Scholar
  222. 222.
    Prasertsawat PO, Herabuty Y, Chaturachinda K. Obstetric analgesia: comparison between tramadol, morphine and pethidine. Curr Ther Res 1986; 40: 1022–8Google Scholar
  223. 223.
    Bitsch M, Emmrich J, Hary J, et al. Obstetrical analgesia with tramadol [in German]. Fortschr Med 1980; 98(16): 632–4PubMedGoogle Scholar
  224. 224.
    Suvonnakote T, Thitadilok W, Atisook R. Pain relief during labour. J Med Assoc Thai 1986; 69(11): 575–80PubMedGoogle Scholar
  225. 225.
    Bredow V. Use of tramadol versus pethidine versus denaverine suppositories in labor: a contribution to noninvasive therapy of labor pain [in German]. Zentralbl Gynakol 1992; 114(11): 551–4PubMedGoogle Scholar
  226. 226.
    Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Anesthesiology 1995; 82(6): 1474–506PubMedGoogle Scholar
  227. 227.
    Krimmer H, Pfeiffer H, Arbogast R, et al. Combined infusion analgesia: an alternative concept in postoperative pain therapy [in German]. Chirurg 1986; 57(5): 327–9PubMedGoogle Scholar
  228. 228.
    Tarradell R, Pol O, Farre M, et al. Respiratory and analgesic effects of meperidine and tramadol in patients undergoing orthopedic surgery. Methods Find Exp Clin Pharmacol 1996; 18(3): 211–8PubMedGoogle Scholar
  229. 229.
    Novikov IA, Kon’kov S, Shumilov EI. Immunity state of oncological patients during long-term treatment with Tramai [in Russian]. Anesteziol Reanimatol 1994; (3): 12–3PubMedGoogle Scholar
  230. 230.
    Bono AV, Cuffari S. Effectiveness and tolerance of tramadol in cancer pain: a comparative study with respect to buprenorphine. Drugs 1997; 53 Suppl. 2: 40–9PubMedGoogle Scholar
  231. 231.
    Brema F, Pastorino G, Martini MC, et al. Oral tramadol and buprenorphine in tumour pain: an Italian multicentre trial. Int J Clin Pharmacol Res 1996; 16(4–5): 109–16PubMedGoogle Scholar
  232. 232.
    Grand S, Zech D, Lynch J, et al. Tramadol: a weak opioid for relief of cancer pain. Pain Clinic 1992; 5(4): 241–7Google Scholar
  233. 233.
    Osipova NA, Novikov GA, Beresnev VA, et al. Analgesic effect of tramadol in cancer patients with chronic pain: a comparison with prolonged-action morphine sulfate. Curr Ther Res 1991; 50(6): 812–21Google Scholar
  234. 234.
    Tawfik MO, Elborolossy K, Nasr F. Tramadol hydrochloride in the relief of cancer pain: a double blind comparison against sustained release morphine [abstract]. Pain 1990; Suppl. 5: S377Google Scholar
  235. 235.
    Wilder-Smith CH, Schimke J, Osterwalder B, et al. Oral tramadol, a mu-opioid agonist and monoamine reuptakeblocker, and morphine for strong cancer-related pain. Ann Oncol 1994; 5(2): 141–6PubMedGoogle Scholar
  236. 236.
    Adler L, McDonald C, O’Brien C, et al. A comparison of oncedaily tramadol with normal release tramadol in the treatment of pain in osteoarthritis. J Rheumatol 2002; 29(10): 2196–9PubMedGoogle Scholar
  237. 237.
    Bird HA, Hill J, Stratford M. A double blind cross-over study comparing the analgesic efficacy of tramadol with pentazocine in patients with osteoarthritis. J Drug Dev Clin Pract 1995; 7: 81–8Google Scholar
  238. 238.
    Goroll D. Tropfenform eines stark wirksamen Analgetikums in der Doppelblindprüfung. Med Klin 1983; 78: 173–5Google Scholar
  239. 239.
    Jensen EM, Ginsberg F. Tramadol versus dextropropoxyphene in the treatment of osteoarthritis. Drug Invest 1994; 8(4): 211–8Google Scholar
  240. 240.
    Pavelka K, Peliskova Z, Stelikova H. Intraindividual differences in pain relief and functional improvement in osteoarthritis with diclofenac or tramadol. Clin Drug Invest 1998; 16(6): 1–9Google Scholar
  241. 241.
    Rauck RL, Ruoff GE, McMillen JI. Comparison of tramadol and acetaminophen with codeine for long-term pain management in elderly patients. CurrTher Res Clin Exp 1994; 55(12): 1417–31Google Scholar
  242. 242.
    Roth SH. Efficacy and safety of tramadol HC1 in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol 1998; 25(7): 1358–63PubMedGoogle Scholar
  243. 243.
    Schnitzer TJ, Gray WL, Paster RZ, et al. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol 2000; 27(3): 772–8PubMedGoogle Scholar
  244. 244.
    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; 24(2): 282–97PubMedGoogle Scholar
  245. 245.
    Sorge J, Stadler T. Comparison of the analgesic efficacy and tolerability of tramadol 100mg sustained-release tablets and tramadol 50mg capsules for the treatment of chronic low back pain. Clin Drug Invest 1997; 14(3): 157–64Google Scholar
  246. 246.
    Wilder-Smith CH, Hill L, Spargo K, et al. Treatment of severe pain from osteoarthritis with slow-release tramadol or dihydrocodeine in combination with NSAIDs: a randomised study comparing analgesia, antinociception and gastrointestinal effects. Pain 2001; 91(1-2): 23–31PubMedGoogle Scholar
  247. 247.
    Göbel H, Stadler T. Treatment of post-herpes zoster pain with tramadol: results of an open pilot study versus clomipramine with or without levomepromazine. Drugs 1997; 53 Suppl. 2: 34–9PubMedGoogle Scholar
  248. 248.
    Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50(6): 1842–6PubMedGoogle Scholar
  249. 249.
    Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999; 83(1): 85–90PubMedGoogle Scholar
  250. 250.
    Lenzhofer R, Moser K. Analgesic effect of tramadol in patients with malignant diseases [in German]. Wien Med Wochenschr 1984; 134(8): 199–202PubMedGoogle Scholar
  251. 251.
    Rodriguez N, Rodriguez Pereira E. Tramadol in cancer pain. Curr Ther Res 1989; 46(6): 1142–8Google Scholar
  252. 252.
    Grond S, Radbruch L, Meuser T, et al. High-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manage 1999; 18(3): 174–9PubMedGoogle Scholar
  253. 253.
    Petzke F, Radbruch L, Sabatowski R, et al. Slow-release tramadol for treatment of chronic malignant pain: an open multicenter trial. Support Care Cancer 2001; 9(1): 48–54PubMedGoogle Scholar
  254. 254.
    Theilade P. Death due to dextropropoxyphene: Copenhagen experiences. Forensic Sci Int 1989; 40: 143–51PubMedGoogle Scholar
  255. 255.
    Ruoff GE. Slowing the initial titration rate of tramadol improves tolerability. Pharmacotherapy 1999; 19(1): 88–93PubMedGoogle Scholar
  256. 256.
    Petrone D, Kamin M, Olson W. Slowing the titration rate of tramadol HCl reduces the incidence of discontinuation due to nausea and/or vomiting: a double-blind randomized trial. J Clin Pharm Ther 1999; 24(2): 115–23PubMedGoogle Scholar
  257. 257.
    Frank M, Sturm M, Arnau H, et al. Quality of life and patient compliance during pain therapy: multicenter study using Tramundin retard [in German]. Fortschr Med 1999; 117(10): 38–9PubMedGoogle Scholar
  258. 258.
    Attal N, Guirimand F, Brasseur L, et al. Effects of IV morphine in central pain: a randomized placebo-controlled study. Neurology 2002; 58(4): 554–63PubMedGoogle Scholar
  259. 259.
    Grond S, Radbruch L, Meuser T, et al. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain 1999; 79(1): 15–20PubMedGoogle Scholar
  260. 260.
    Apaydin S, Uyar M, Karabay NU, et al. The antinociceptive effect of tramadol on a model of neuropathic pain in rats. Life Sci 2000; 66(17): 1627–37PubMedGoogle Scholar
  261. 261.
    Tsai YC, Sung YH, Chang PJ, et al. Tramadol relieves thermal hyperalgesia in rats with chronic constriction injury of the sciatic nerve. Fundam Clin Pharmacol 2000; 14(4): 335–40PubMedGoogle Scholar
  262. 262.
    Olligs J, Anderson A. Schmerybehandlung mit Tramadol Retard bei Neuropathie [abstract]. Schmerz 1997; Suppl. 1: 49Google Scholar
  263. 263.
    Harati Y, Gooch C, Swenson M, et al. Maintenance of the longterm effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications 2000; 14(2): 65–70PubMedGoogle Scholar
  264. 264.
    Grond S, Zech D, Schug SA, et al. Validation of World Health Organization guidelines for cancer pain relief during the last days and hours of life. J Pain Symptom Manage 1991; 6: 411–22PubMedGoogle Scholar
  265. 265.
    World Health Organization: Cancer pain relief. Geneva: World Health Organization, 1996Google Scholar
  266. 266.
    Mercadante S. Pain treatment and outcomes for patients with advanced cancer who receive follow-up care at home. Cancer 1999; 85(8): 1849–58PubMedGoogle Scholar
  267. 267.
    Zech DF, Grond S, Lynch J, et al. Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 1995; 63: 65–76PubMedGoogle Scholar
  268. 268.
    Eisenberg E, Berkey CS, Carr DB, et al. Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a metaanalysis. J Clin Oncol 1994; 12: 2756–65PubMedGoogle Scholar
  269. 269.
    Grond S, Meuser T. Weak opioids: an educational substitute for morphine? Curr Opin Anaesthesiol 1998; 11: 559–65PubMedGoogle Scholar
  270. 270.
    Cossmann M, Kohnen C, Langford R, et al. Tolerance and safety of tramadol use: results of international studies and data from drug surveillance. Drugs 1997; 53 Suppl. 2: 50–62PubMedGoogle Scholar
  271. 271.
    Schaffer J, Piepenbrock S, Kretz FJ, et al. Nalbuphine and tramadol for the control of postoperative pain in children [in German]. Anaesthesist 1986; 35(7): 408–13PubMedGoogle Scholar
  272. 272.
    Barnung SK, Treschow M, Borgbjerg FM. Respiratory depression following oral tramadol in a patient with impaired renal function. Pain 1997; 71(1): 111–2PubMedGoogle Scholar
  273. 273.
    Maier C, Kibbel K, Mercker S, et al. Postoperative pain therapy at general nursing stations: an analysis of eight year’s experience at an anesthesiological acute pain service [in German]. Anaesthesist 1994; 43(6): 385–97PubMedGoogle Scholar
  274. 274.
    Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000; 20(12): 1423–31PubMedGoogle Scholar
  275. 275.
    Potschka H, Friderichs E, Loscher W. Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its Ml metabolite in the rat kindling model of epilepsy. Br J Pharmacol 2000; 131(2): 203–12PubMedGoogle Scholar
  276. 276.
    Gasse C, Derby L, Vasilakis-Scaramozza C, et al. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy 2000; 20(6): 629–34PubMedGoogle Scholar
  277. 277.
    Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999; 57(1): 7–22PubMedGoogle Scholar
  278. 278.
    Preston KL, Jasinski DR, Testa M. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 1991; 27(1): 7–17PubMedGoogle Scholar
  279. 279.
    Cami J, Lamas X, Farre M. Acute effects of tramadol in methadone-maintained volunteers. Drugs 1994; 47 Suppl. 1: 39–43PubMedGoogle Scholar
  280. 280.
    Spiller HA, Gorman SE, Villalobos D, et al. Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997; 35(4): 361–4PubMedGoogle Scholar
  281. 281.
    Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997; 31(2): 175–7PubMedGoogle Scholar
  282. 282.
    Egberts AC, ter Borgh J, Brodie-Meijer CC. Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997; 12(3): 181–2PubMedGoogle Scholar
  283. 283.
    Lantz MS, Buchalter EN, Giambanco V. Serotonin syndrome following the administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998; 13(5): 343–5PubMedGoogle Scholar
  284. 284.
    Goeringer KE, Logan BK, Christian GD. Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers. J Anal Toxicol 1997; 21(7): 529–37PubMedGoogle Scholar
  285. 285.
    Ripple MG, Pestaner JP, Levine BS, et al. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol 2000; 21(4): 370–4PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Department of AnesthesiaMartin-Luther-UniversityHalle-WittenbergGermany
  2. 2.Universitätsklinik für Anästhesiologie und Operative IntensivmedizinMartin-Luther-Universität Halle-WittenbergHalleGermany

Personalised recommendations