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Tramadol

A Review of its Use in Perioperative Pain

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Summary

Abstract

Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action, acting as both a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. The 2 enantiomers of racemic tramadol function in a complementary manner to enhance the analgesic efficacy and improve the tolerability profile of tramadol.

In several comparative, well designed studies, oral and parenteral tramadol effectively relieved moderate to severe postoperative pain associated with surgery. Its overall analgesic efficacy was similar to that of morphine or alfentanil and superior to that of pentazocine. Tramadol provided effective analgesia in children and in adults for both inpatient and day surgery.

Tramadol was generally well tolerated in clinical trials. The most common adverse events (incidence of 1.6 to 6.1%) were nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses in adults or children. Tramadol also has a low potential for abuse or dependence.

Conclusions: The efficacy of tramadol for the management of moderate to severe postoperative pain has been demonstrated in both inpatients and day surgery patients. Most importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters. Tramadol may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, the obese and smokers, in patients with impaired hepatic or renal function, and in patients in whom nonsteroidal anti-inflammatory drugs are not recommended or need to be used with caution. Parenteral or oral tramadol has proved to be an effective and well tolerated analgesic agent in the perioperative setting.

Pharmacodynamic Profile

Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action. It is both a weak opioid agonist with selectivity for the μ-receptor and a weak inhibitor of the reuptake of noradrenaline (norepi-nephrine) and serotonin (5-hydroxytryptamine; 5-HT). This dual mechanism of action may be attributed to the 2 enantiomers of racemic tramadol. The (+)-enantiomer has a higher affinity for the μ-receptor and is a more effective inhibitor of 5-HT reuptake, whereas the (−)-enantiomer is a more effective inhibitor of noradrenaline reuptake and increases its release by autoreceptor activation.

In healthy volunteers, oral tramadol 100mg provided superior analgesia compared with placebo. The peak analgesic effect occurred 1 to 4 hours after drug administration, with analgesia persisting for 3 to 6 hours.

Tramadol is extensively metabolised in the liver, with the O-desmethyl (M1) metabolite of tramadol having an ≈200-fold higher affinity for opioid receptors than the parent drug. The O-desmethylation of tramadol is dependent on the cytochrome P450 enzyme CYP2D6 sparteine-oxygenase (deficient in ≈8% of Caucasians). Studies in healthy volunteers deficient in this enzyme (poor tramadol metabolisers) provided evidence for the possible contribution of the M1 metabolite to the analgesic effects of tramadol, with reduced analgesia in poor metabolisers compared with extensive metabolisers.

The two enantiomers of tramadol act synergistically to provide analgesia. In both clinical and animal studies, the (+)-enantiomer provided similar analgesia to that of racemic tramadol and superior analgesia compared with the (−)-enantiomer. However, racemic tramadol showed an improved tolerability profile compared with the (+)-enantiomer in these studies.

Several comparative, double-blind studies, in both adults and children, indicated that unlike other opioids (such as morphine, pethidine, oxycodone and nalbuphine) postoperative tramadol was not associated with clinically relevant respiratory depression. In addition, although one study demonstrated a statistically significant increase in both systolic and diastolic blood pressure, these were not considered clinically relevant. There were also no clinically relevant effects on heart rate with tramadol and it reduced shivering in postoperative patients.

Pharmacokinetic Profile

Tramadol is rapidly absorbed following single or multiple oral 100mg doses in adult volunteers. The mean absolute bioavailability of tramadol was ≈68% and increased to >90% with multiple doses and with intramuscular administration. Food intake had no clinically relevant effects on its bioavailability. In healthy adult volunteers administered a lOOmg single oral dose of tramadol, the maximum plasma concentration (Cmax) was 308 μg/L at 1.6 hours and with a single intramuscular dose was 193 μg/L attained at 0.75 hours. Cmax for the M1 metabolite after a single oral 100mg dose was 55 μg/L and was reached in ≈3 hours. Tramadol has a high tissue affinity, with an apparent volume of distribution after parenteral administration of ≈260L.

Tramadol undergoes extensive first-pass metabolism in the liver, with ≈10 to 30% of an oral dose excreted unmetabolised in healthy volunteers. Both tramadol and its metabolites are primarily excreted via the kidneys (90%). The terminal elimination half-life (t½β) value for tramadol after a single oral (100mg) or parenteral (50mg) dose was ≈5.5 hours. t½β values for the M1 metabolite following oral single or multiple 100mg doses were 6.69 and 6.98 hours, respectively. t½β is increased ≈2-fold in patients with renal or hepatic impairment. Concomitant administration with carbamazepine, an inducer of hepatic enzymes, reduced the t½β of tramadol by ≈50%.

Clinical Efficacy

The analgesic efficacy of intravenous, intramuscular and oral tramadol has been established in several randomised, double-blind, parallel-group, comparative studies in adult patients with moderate to severe acute postoperative pain, and in a limited number of studies in paediatric patients.

Parenteral or oral tramadol effectively relieved moderate to severe postoperative pain associated with several types of surgery (including abdominal, orthopaedic and cardiac surgery), reducing pain intensity by 46.8 to 57.6% within 4 to 6 hours (assessed using a 100mm or 100-point visual analogue scale). There is also a dose-dependent reduction in the severity and prevalence of postoperative shivering with tramadol treatment.

The overall analgesic efficacy with tramadol was comparable to that achieved using equianalgesic doses of parenteral morphine or alfentanil. Intramuscular tramadol also provided similar efficacy compared with intramuscular ketorolac in postoperative patients.

Concomitant use of intravenous tramadol 50 or 100mg with dipyrone 25 or 50mg (a nonsteroidal anti-inflammatory drug; NSAID) using patient controlled analgesia provided better analgesia than intravenous piritramide 0.75 or 1.5mg (an opioid agent). A continuous infusion of tramadol 10 mg/h with concomitant oral propacetamol 2g 4 times daily achieved superior analgesic efficacy compared with tramadol monotherapy.

In children, intramuscular tramadol 2 mg/kg as required provided analgesia similar to that of intramuscular pethidine 1 mg/kg or nalbuphine 0.1 mg/kg following lower abdominal surgery. Furthermore, a single caudal injection of tramadol 2 mg/kg provided similar analgesia 3 to 12 hours postoperatively to that of caudal bupivacaine 2 mg/kg (a local anaesthetic) or tramadol 2 mg/kg with concomitant bupivacaine 2 mg/kg, although at the 3-hour time point bupivacaine provided superior analgesia.

Tramadol provided effective postoperative pain relief in patients after day surgery (including groin and gynaecological surgery). The majority of these studies involved complex treatment regimens, with the concomitant administration (pre-, intra-and/or postoperatively) of several other analgesic agents (both opioids and NSAIDs). In a large multicentre study, perioperative intravenous and oral tramadol 100mg provided superior analgesic efficacy for the first 24 hours compared with a combination of intraoperative fentanyl 100μg and postoperative oral codeine 16mg/paracetamol 1000mg. Tramadol 100mg (administered intra-and post-operatively) also provided similar analgesic efficacy compared with naproxen sodium 500mg in 91 patients. Furthermore, intravenous tramadol 1.5 mg/kg, administered at the induction of anaesthesia, provided superior pain relief compared with intravenous ketorolac 10mg in 60 patients after laparoscopic surgery.

Results from early studies investigating the intraoperative use of tramadol were controversial, with reports of increased recall of intraoperative events following its use. However, several recent studies using volatile or intravenous anaesthetic techniques, in both inpatients and day surgery patients, have not shown any clinically significant lightening of anaesthesia depth sufficient to cause accidental awareness while undergoing surgery.

Tolerability

In general, tramadol was well tolerated in clinical trials. The most common adverse events with single or multiple dose oral or parenteral administration of tramadol were nausea (6.1% of patients), dizziness (4.6), drowsiness (2.4), tiredness (2.3), sweating (1.9), vomiting (1.7) and dry mouth (1.6). Adverse events occurred in ≈15% of patients. Unlike other opioids, notably morphine, tramadol did not cause clinically relevant respiratory depression at recommended therapeutic doses. The incidence of seizures in patients receiving tramadol is estimated to be <1%.

The risk of dependence or abuse with tramadol is low (0.7 to 1.5 cases of abuse per 100 000 individuals). The most common symptoms associated with an overdose were lethargy (30% of patients), nausea (14%), tachycardia (13%), agitation (10%), seizures (8%), coma (5%), hypertension (5%) and respiratory depression (2%). Naloxone treatment reversed sedation and apnoea in 50% of patients. No serious cardiotoxicity was observed with tramadol overdose.

Dosage and Administration

Tramadol is recommended for the management of acute or chronic moderate to severe pain. In adults and adolescents, the usual dosage is 50 to 100mg every 4 to 6 hours as required, with a maximum dosage of 400 mg/day. It may be administered orally or parenterally, although only an oral formulation is available in the US. Dosage adjustments may be required in patients with renal or hepatic impairment and in those >75 years of age. Recommendations for the use of tramadol in paediatric patients may vary between individual countries. For example, tramadol is not recommended for use in children <12 years of age in the UK or in those <16 years of age in the US, whereas in Germany some formulations are approved for use in children aged ≥1 year.

Tramadol is not recommended in patients receiving monoamine oxidase inhibitors and is contraindicated in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. The risk of seizure with tramadol administration may be enhanced in patients receiving monoamine oxidase inhibitors, neuroleptics, other drugs that reduce the seizure threshold, patients with epilepsy or patients otherwise at risk of seizure. Tramadol should be used with caution in patients with increased intracranial pressure and when treating patients with respiratory depression or if concomitant central nervous system depressant agents are being administered. When used with concomitant carbamazepine, dosages of tramadol may require adjustment.

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References

  1. 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 Aug; 46: 313–40

    Article  PubMed  CAS  Google Scholar 

  2. Bamigbade TA, Langford RM. Tramadol hydrochloride: an overview of current use. Hosp Med 1998 May; 59: 373–6

    PubMed  CAS  Google Scholar 

  3. Barkin RL. Focus on tramadol: a centrally acting analgesic for moderate to moderately severe pain. Formulary 1995 Jun; 30: 321–5

    Google Scholar 

  4. Abel SR. Tramadol: an alternative analgesic to traditional opioids and NSAIDs. J Pharm Care Pain Symptom Control 1995; 3(1): 5–29

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  6. 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 Sep; 79: 352–6

    Article  PubMed  CAS  Google Scholar 

  7. 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 Mar; 108: 806–11

    Article  PubMed  CAS  Google Scholar 

  8. Frink MC, Hennies H-H, Englberger W, et al. Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 1996 Nov; 46: 1029–36

    PubMed  CAS  Google Scholar 

  9. Desmeules JA, Piguet V, Collart L, et al. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996 Jan; 41: 7–12

    Article  PubMed  CAS  Google Scholar 

  10. Driessen B, Reimann W. Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 1992; 105: 147–51

    Article  PubMed  CAS  Google Scholar 

  11. Houmes RM, 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: 510–4

    Article  PubMed  CAS  Google Scholar 

  12. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998 Jan; 15: 64–8

    PubMed  CAS  Google Scholar 

  13. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth 1997 Nov; 9: 582–5

    Article  PubMed  CAS  Google Scholar 

  14. Vickers MD, O’Flaherty D, Szekely SM, et al. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia 1992; 47: 291–6

    Article  PubMed  CAS  Google Scholar 

  15. Schaffer J, Piepenbrock S, Kretz FJ, et al. Nalbuphine and trmadol for control of postoperative pain in children. An-aesthesist 1986; 35: 408–13

    CAS  Google Scholar 

  16. Bösenberg AT, Ratcliffe S. The respiratory effects of tramadol in children under halothane anaesthesia. Anaesthesia 1998 Oct; 53: 960–4

    Article  PubMed  Google Scholar 

  17. De-Witte JL, Kim JS, Sessler DI, et al. Tramadol reduces the sweating, vasoconstriction, and shivering thresholds. Anesth Analg 1998 Jul; 87: 173–9

    PubMed  CAS  Google Scholar 

  18. Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol 1997 Jan; 43: 71–5

    Article  PubMed  CAS  Google Scholar 

  19. Murphy DB, Sutton A, Prescott LF, et al. A comparison of the effects of tramadol and morphine on gastric emptying in man. Anaesthesia 1997 Dec; 52: 1224–9

    Article  PubMed  CAS  Google Scholar 

  20. Elton CD, Guest C, Pallett EJ, et al. Effect of tramadol on gastric emptying of a liquid meal [abstract]. Br J Anaesth 1999 Mar; 82: 471P

    Google Scholar 

  21. Crighton IM, Martin PH, Hobbs GJ, et al. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric empyting in human volunteers. Anesth Analg 1998 Aug; 87: 445–9

    PubMed  CAS  Google Scholar 

  22. 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 Sep; 91: 639–47

    Article  PubMed  CAS  Google Scholar 

  23. Raffa RB, Friderichs E, Reimann W, et al. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993 Oct; 267: 331–40

    PubMed  CAS  Google Scholar 

  24. Sevcik J, Nieber K, Driessen B, et al. Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones. Br J Pharmacol 1993 Sep; 110: 169–76

    Article  PubMed  CAS  Google Scholar 

  25. 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 Sep; 62: 313–20

    Article  PubMed  CAS  Google Scholar 

  26. Kogel B, Engelberger W, Hennies H-H, et al. Involvement of metabolites in the analgesic action of tramadol [abstract no.60]. In: 9th World Congress onPain: 1999 22–27 Aug: Vienna: 523

  27. De Jong RH. Comment on the hypoalgesic effect of tramadol in relation to CYP2D6 [comment]. Pain Dig 1997; 7(4): 245

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Dayer P, Collart L, Desmeules J. The pharmacology of tramadol. Drugs 1994; 47 Suppl. 1: 3–7

    Article  PubMed  CAS  Google Scholar 

  30. Minto CF, Power I. New opioid analgesics: an update. Int Anesthesiol Clin 1997 Spring; 35: 49–65

    Article  PubMed  CAS  Google Scholar 

  31. Giusti P, Buriani A, Cima L, et al. Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes. Br J Pharmacol 1997 Sep; 122: 302–6

    Article  PubMed  CAS  Google Scholar 

  32. Praesertsawat PO, Herabutya Y, Chaturachinda K. Obstetric analgesia: comparison between tramadol, morphine and pethidine. Curr Ther Res 1986; 40(6): 1022–8

    Google Scholar 

  33. Parth P, Madler C, Morawetz RF. Analgesic effects of pethidine and tramadol as assessed by experimentally induced pain in man: a double-blind comparison [in German]. Anaesthesist 1984; 33: 235–9

    PubMed  CAS  Google Scholar 

  34. Budd K, Langford R. Tramadol revisisted. Br J Anaesth 1999 Apr; 82: 493–5

    Article  PubMed  CAS  Google Scholar 

  35. 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): 212–20

    Article  PubMed  CAS  Google Scholar 

  36. Spiller HA, Gorman SE, Villalobos D, et al. Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997 Jun; 35: 361–4

    Article  PubMed  CAS  Google Scholar 

  37. Langford RM, Bakhshi KN, Moylan S et al. Hypoxaemia after lower abdominal surgery: comparison of tramadol and morphine. Int J Acute Pain Manage 1998 Mar; 1: 7–12

    Article  CAS  Google Scholar 

  38. Manocha A, Sharma KK, Mediratta PK. Tramadol, a centrally acting opioid: anticonvulsant effect against maximal electro-shock seizure in mice. Indian J Physiol Pharmacol 1998 Jul; 42: 407–11

    PubMed  CAS  Google Scholar 

  39. Kazmierczak R, Coley KC. Impact of Dear Doctor letters on prescribing: evaluation of the use of tramadol HC1. Formulary 1997; 32: 977–8

    Google Scholar 

  40. Jick H, Derby LE, Vasilakis C, et al. The risk of seizures associated with tramadol. Pharmacotherapy 1998 May–Jun; 18: 607–11

    PubMed  CAS  Google Scholar 

  41. Lintz W, Beier H, Gerloff J. Absolute bioavailability of tramadol after intramuscular administration of Tramal®-50 solution for injection in 12 male volunteers [abstract]. 7th World Congr Pain 1993 Aug 22: 537–8

    Google Scholar 

  42. Liao S, Hill JF, Nayak RK. Pharmacokinetics of tramadol following single and multiple oral doses in man [abstract no. 8206]. Pharm Res 1992; 9 Suppl.: 308

    Google Scholar 

  43. Tegeder I, Lötsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 1999 Jul; 37: 17–40

    Article  PubMed  CAS  Google Scholar 

  44. Lintz W, Barth H, Osterloh G, et al. Pharmacokinetics of tramadol and bioavailability of enterai tramadol formulations. 3rd communication: suppositories. Arzneimittelforschung 1998 Sep; 48: 889–99

    CAS  Google Scholar 

  45. Lintz W, Barth H, Becker R, et al. Pharmacokinetics of tramadol and bioavailability of enterai tramadol formulations. 2nd communication: drops with ethanol. Arzneimittelforschung 1998 May; 48: 436–45

    CAS  Google Scholar 

  46. 1997 Physicians GenRx. Tramadol hydrochloride. In: Mosby’s Complete Drug Reference. 7th ed. Missouri:, 1997: II-2026-8

  47. Liao S, Hills J, Stubbs RJ, et al. The effect of food on the bioavailablity of tramadol [abstract no. 8207]. Pharm Res 1992; 9 Suppl.: 308

    Google Scholar 

  48. Ortho Pharmaceuticals. Ultram; prescribing information. New Jersey, US, 1995

  49. American Society of Hospital Pharmacists. Tramadol hydrochloride. In: McEvoy GK, editor. American Hospital Formulary Services Drug Information 1999. Bethesda: Datapharma Publications Limited, 1999: 1809–12

    Google Scholar 

  50. Searle. Zydol ampoules; prescribing information. In: Walker W, editor. ABPI compendium of data sheets and summaries of product characteristics. London: Datapharm Publications Limited, 1998-1999: 1290–1

    Google Scholar 

  51. Gaynes BI, Barkin RI. Analgesics in ophthalmic practice: a review of the oral non-narcotic agent tramadol. Optom Vis Sci 1999; 76: 455–61

    Article  PubMed  CAS  Google Scholar 

  52. Paar WD, Poche S, Gerloff J, et al. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 1997 Nov-Dec; 53: 235–9

    Article  PubMed  CAS  Google Scholar 

  53. Wu W-N, Desai D, McKown LA, et al. Metabolism of Ultram® (tramadol) in the dog [abstract]. 6th ISSX 1997 Jun 30, Gothenburg, Sweden: 160

  54. Murthy BVS, Pandya KS, Booker PD, et al. Pharmacokinetics of tramadol in children after i.V. or caudal epidural administration. Br J Anaesth 2000; 84(3): 346–9

    CAS  Google Scholar 

  55. Searle. Zydol capsules; prescribing information. In: Walker W, editor. ABPI compendium of data sheets and summary of product characteristics. London: Datapharma Publications Limited, 1998-1999: 1291

    Google Scholar 

  56. Boeijinga JK, van Meegen E, van den Ende R, et al. Lack of interaction between tramadol and coumarins. J Clin Pharmacol 1998 Oct; 38: 966–70

    PubMed  CAS  Google Scholar 

  57. Madsen H, Rasmussen JM, Brøsen K. Interaction between tramadol and phenprocoumon. Lancet 1997 Aug 30; 350: 637

    Article  PubMed  CAS  Google Scholar 

  58. Boeijinga JK, van Meegen E, van den Ende R, et al. Is there interaction between tramadol and phenprocoumon? [letter; comment]. Lancet 1997 Nov 22; 350: 1552–3

    Article  PubMed  CAS  Google Scholar 

  59. Scher ML, Huntington NH, Vitillo JA. Potential interaction between tramadol and warfarin [letter]. Ann Pharmacother 1997 May; 31: 646–7

    PubMed  CAS  Google Scholar 

  60. Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy 1998 Jul–Aug; 18: 871–3

    PubMed  CAS  Google Scholar 

  61. Famciclovir, a competitor to acyclovir in shingles/Tramadol, a new analgesic. Int Pharm J 1994 Nov–Dec; 8: 242–5

    Google Scholar 

  62. Portenoy RK, Lesage P. Management of cancer pain. Lancet 1999 May 15; 353: 1695–700

    Article  PubMed  CAS  Google Scholar 

  63. McQuay H, Carroll D, Moore A. Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems. Pain 1995; 64: 331–5

    Article  Google Scholar 

  64. Jamison RN. Comprehensive pretreatment and outcome assessment for chronic opioid therapy in nonmalignant pain. J Pain Symptom Manage 1996 Apr; 11: 231–41

    Article  PubMed  CAS  Google Scholar 

  65. Montauk SL, Martin J. Treating chronic pain. Am Fam Physician 1997 Mar; 55: 1151–60

    PubMed  CAS  Google Scholar 

  66. Wulf H, Neugebauer E, Maier C. Practice guidelines for the management of acute pain. Int J Acute Pain Manage 1997 Dec; 1: 41–5

    Article  Google Scholar 

  67. US Department of Health and Human Services Food and Drug Administration. Guideline for the evaluation of analgesic drugs.: Food and Drug Administration, 1992; 1–9

  68. US Department of Health and Human Services Food and Drug Administration. Clinical development programs for drugs, devices and biological products intended for the treatment of osteoarthritis (OA).: Food and Drug Administration, 1999

  69. Hannallah RS, Broadman LM, Belman AB, et al. Comparison of caudal and ilioinguinal/iliohypogastric nerve blocks for control of post-orchiopexy pain in pediatric ambulatory surgery. Anesthesiology 1987; 66: 832–4

    Article  PubMed  CAS  Google Scholar 

  70. 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): 9–16

    PubMed  CAS  Google Scholar 

  71. Colletti V, Carner M, Vincenzi A, et al. Intramuscular tramadol versus ketorolac in the treatment of pain following nasal surgery: a controlled multicenter trial. Curr Ther Res Clin Exp 1998 Sep; 59: 608–18

    Article  CAS  Google Scholar 

  72. Lanzetta A, Vizzardi M, Letizia G, et al. Intramusculartramadol versus ketorolac in patients with orthopedic and traumatologie postoperative pain: a comparative multicenter trial. Curr Ther Res Clin Exp 1998 Jan; 59: 39–47

    Article  CAS  Google Scholar 

  73. Manji M, Rigg C, Jones P, et al. Tramadol for post operative analgesia in coronary artery bypass graft surgery [abstract]. Br J Anaesth 1997 Jun; 78 Suppl. 2: 44

    Google Scholar 

  74. Sellin M, Louvard V, Sicsic JC, et al. Postoperative pain: tramadol vs morphine after cardiac surgery [abstract]. Br J Anaesth 1998 Jun; 80 Suppl. 2: 41

    Google Scholar 

  75. 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): 87–92

    PubMed  CAS  Google Scholar 

  76. Kupers R, Callebaut V, Debois V, et al. Efficacy and safety of oral tramadol and pentazocine for postoperative pain following prolapsed intervertébral disc repair. Acta Anaesthesiol Belg 1995; 46: 31–7

    PubMed  CAS  Google Scholar 

  77. Siddik-Sayyid S, Aouad-Maroun M, Sleiman D, et al. Epidural tramadol for postoperative pain after Cesarean section. Can J Anesth 1999 Aug; 46: 731–5

    Article  PubMed  CAS  Google Scholar 

  78. Jeffrey HM, Charlton P, Mellor DJ, et al. Analgesia after intracranial surgery: a double-blind, prospective comparison of codeine and tramadol. Br J Anaesth 1999 Aug; 83: 245–9

    Article  PubMed  CAS  Google Scholar 

  79. Vickers MD, Paravicini D. Comparison of tramadol with morphine for post-operative pain following abdominal surgery. Eur J Anaesthesiol 1995 May; 12: 265–71

    PubMed  CAS  Google Scholar 

  80. Sunshine A, Olson NZ, Zighelboim I, et al. Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clin Pharmacol Ther 1992; 51: 740–6

    Article  PubMed  CAS  Google Scholar 

  81. Ilias W, Jansen M. Pain control after hysterectomy: an observer-blind, randomised trial of lornoxicam versus tramadol. Br J Clin Pract 1996 Jun; 50: 197–202

    PubMed  CAS  Google Scholar 

  82. Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain 1997 Feb; 69: 287–94

    Article  PubMed  CAS  Google Scholar 

  83. Gadalla EF. Tramadol hydrochloride (Tramai) versus morphine for postoperative pain relief [abstract no.248]. 9th World Congress on Pain; 1999 Aug 22–27; Vienna, 75–76

  84. Rud U, Fischer MV, Mewes R, et al. Postoperative analgesia with tramadol: continuous infusion versus repetitive bolus administration [in German]. Anaesthesist 1994 May; 43: 316–21

    Article  PubMed  CAS  Google Scholar 

  85. Hartjen K, Fischer MV, Mewes R, et al. Preventive analgesia. Preventive tramadol infusion in comparison with bolus application on demand during the early postoperative period [in German]. Anaesthesist 1996 Jun; 45: 538–44

    CAS  Google Scholar 

  86. Chan AMH, Ng KFJ, Tong EWN, et al. Control of shivering under regional anesthesia in obstetric patients with tramadol. Can J Anaesth 1999 Mar; 46: 253–8

    Article  PubMed  CAS  Google Scholar 

  87. de Witte J, Deloof T, de Veylder J, et al. Tramadol in the treatment of postanesthetic shivering. Acta Anaesthesiol Scand 1997 Apr; 41: 506–10

    Article  PubMed  Google Scholar 

  88. Trekova N, Bunatian A, Zolicheva N. Tramadol hydrochloride in the management of postoperative shivering: a double-blind trial with placebo [abstract no.264]. In: 9th World Congress on Pain: 1999 Aug 22–27: Vienna, 337

  89. Owen H, Plummer J. Patient-controlled analgesia: current concepts in acute pain management. CNS Drugs 1997 Sep; 8: 203–18

    Article  CAS  Google Scholar 

  90. 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 Dec; 45: 1168–75

    CAS  Google Scholar 

  91. Pang WW, Mok MS, Huang PY. Combination of lysine acetyl salicylate and tramadol for post operative analgesia. Anesth Analg 1999 Feb; 88 Suppl.: abstr. S223

    Article  Google Scholar 

  92. Pang W-W, Mok MS, Lin C-H, et al. Comparison of patient-controlled analgesia (PCA) with tramadol or morphine. Can J Anesth 1999; 46(11): 1030–5

    Article  PubMed  CAS  Google Scholar 

  93. Silvasti M, Svartling N, Pitkänen M. Comparison of morphine and tramadol in patient-controlled analgesia after microvascular breast reconstruction [abstract]. Br J Anaesth 1998 May; 80 Suppl. 1: 178

    Google Scholar 

  94. 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 Nov; 14: 646–54

    Article  PubMed  CAS  Google Scholar 

  95. Tarkkila P, Silvasti M, Tuominen M, et al. Efficacy and side effects of tramadol and oxycodone after maxillofacial surgery [abstract]. Can J Anaesth 1998 May; 45 (Pt 2): A19

    Article  Google Scholar 

  96. Rodriguez MJ, De La Torre MR, Perez-Iraola P, et al. Comparative study of tramadol versus NSAIDs as intravenous continuous infusion for managing postoperative pain. Curr Ther Res 1993 Oct; 54: 375–83

    Article  Google Scholar 

  97. Likar R, Jost R, Mathiaschitz K, et al. Postoperative patient controlled analgesia using a low-tech PCA system. Int J Acute Pain Manage 1999 Mar; 2: 17–26

    Article  Google Scholar 

  98. Migliorini F, Tropea F, Perciaccante L, et al. Tramadol in PCA plus propacetamol is a good choice after major orthopaedic surgery [abstract]. Br J Anaesth 1999 Jun; 82 Suppl. 1: 190

    Google Scholar 

  99. Roelofse JA, Payne KA. Oral tramadol: analgesic efficacy in children following multiple dental extractions. Eur J Anaesthesiol 1999; 16: 441–7

    PubMed  CAS  Google Scholar 

  100. Prosser DP, Davis A, Booker PD, et al. Caudal tramadol for postoperative analgesia in paediatric hypospadias surgery. Br J Anaesth 1997 Sep; 79: 293–6

    Article  PubMed  CAS  Google Scholar 

  101. 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 May; 37: 238–42

    PubMed  CAS  Google Scholar 

  102. Barsoum MW. Comparison of the efficacy and tolerability of tramadol, pethidine and nalbuphine in children with postoperative pain: an open randomised study. Clin Drug Invest 1995 Apr; 9: 183–90

    Article  Google Scholar 

  103. Lehmann KA, Horrichs G, Hoeckle W. Tramadol as an intraoperative analgesic: a randomised double-blind study with placebo [in German]. Anaesthesist 1985; 34: 11–9

    PubMed  CAS  Google Scholar 

  104. Bamigbade TA, Langford RM, Blower AL, et al. Pain control in day surgery: tramadol vs standard analgesia [abstract]. Br J Anaesth 1998 Apr; 80: 558P-9P

    Google Scholar 

  105. Coetzee JF, Maritz JS, du TJC. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1996 Mar; 76: 415–8

    Article  PubMed  CAS  Google Scholar 

  106. Coetzee JF, van Loggerenberg H. Tramadol or morphine administered during operation: a study of immediate postoperative effects after abdominal hysterectomy. Br J Anaesth 1998 Nov; 81: 737–41

    Article  PubMed  CAS  Google Scholar 

  107. De Witte J, Rietman GW, Vandenbroucke G, et al. Post-operative effects of tramadol administered at wound closure. Eur J Anaesthesiol 1998 Mar; 15: 190–5

    PubMed  Google Scholar 

  108. James MFM, Heijke SAM, Gordon PC. Intravenous tramadol versus epidural morphine for postthoracotomy pain relief: a placebo-controlled double-blind trial. Anesth Analg 1996 Jul; 83: 87–91

    PubMed  CAS  Google Scholar 

  109. Lauretti GR, Mattos AL, Lima I. Tramadol and beta-cyclodextrin piroxicam: effective multimodal balanced analgesia for the intra-and postoperative period. Reg Anesth 1997 May–Jun; 22: 243–8

    Article  PubMed  CAS  Google Scholar 

  110. Raff M. The comparison of continuous intravenous tramadol and morphine sulphate for postoperative analgesia. Int J Acute Pain Manage 1998 Dec; 1: 7–10

    CAS  Google Scholar 

  111. Halfpenny DM, Callado LF, Stamford JA. Is tramadol an anti-depressant? [letter]. Br J Anaesth 1999 Mar; 82: 480–1

    Article  PubMed  CAS  Google Scholar 

  112. Vaughan DJA, Shinner G, Thornton C, et al. Tramadol: effects on depth of anaesthesia as measured by the auditory evoked response [abstract no. A40]. Anaesthesia 1999; 82 Suppl. l: 12

    Google Scholar 

  113. Peters AAW, Witte EH, Damen ACH, 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. Eur J Obstet Gynecol Reprod Biol 1996 May; 66: 51–6

    Article  PubMed  CAS  Google Scholar 

  114. Putland AJ, McCluskey A. The analgesic efficacy of tramadol versus ketorolac in day-case laparoscopic sterilisation. Anaesthesia 1999 Apr; 54: 382–5

    Article  PubMed  CAS  Google Scholar 

  115. Broome IJ, Robb HM, Raj N, et al. The use of tramadol following day-case oral surgery. Anaesthesia 1999 Mar; 54: 289–92

    Article  PubMed  CAS  Google Scholar 

  116. 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 Jul; 52: 649–52

    Article  PubMed  CAS  Google Scholar 

  117. Cossmann M, Kohnen C, Langford R, et al. Tolerance and safety of tramadol: results of international studies and drug control data [in French]. Drugs 1997; 53 Suppl. 2: 50–62

    Article  PubMed  Google Scholar 

  118. Hopkins D, Shipton EA, Potgieter D, et al. Comparison of tramadol and morphine via subcutaneous PCA following major orthopaedic surgery. Can J Anaesth 1998 May; 45 (Pt 1): 435–42

    Article  PubMed  CAS  Google Scholar 

  119. Cossmann M, Wilsmann KM. Effect and side-effects of tramadol: an open phase IV study with 7198 patients [in German]. Therapiewoche 1987; 37: 3475–85

    Google Scholar 

  120. Cossmann M, Wilsmann KM. Use of tramadol injection (Tramal) for acute pain: open study to assess efficacy and tolerability of a single parenteral dose [in German]. Munch Med Wochenschr 1988; 130: 633–6

    Google Scholar 

  121. Cossmann M, Wilsmann KM. Treatment of prolonged pain: assessment of the efficacy and safety of repeated administration of tramadol (tramai). Munch Med Wochenschr 1987: 851–4

  122. Menghini F, Van Deenen D, Berger A, et al. Postoperative tramadol vs. diclofenac and propacetamol in paediatric tonsillectomy: comparison of efficacy and side effects [abstract]. Br J Anaesth 1999 Jun; 82 Suppl. 1: 153

    Google Scholar 

  123. Egberts ACG, ter Borgh J, Brodie-Meijer CCE. Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997 May; 12: 181–2

    Article  PubMed  CAS  Google Scholar 

  124. Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997 Feb; 31: 175–7

    PubMed  CAS  Google Scholar 

  125. Lantz MS, Buchalter EN, Giambanco V. Serotonin syndrome following the administration of tramadol with paroxetine [letter]. Int J Geriatr Psychiatry 1998 May; 13: 343–5

    Article  PubMed  CAS  Google Scholar 

  126. 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: 7–22

    Article  PubMed  CAS  Google Scholar 

  127. Bayer Vital. Tramadol basic drops; prescribing information [in German]. In: Gelbe Liste Pharmindex. Fulda: Parzeller GmbH and Company KG, 1999: 2199

    Google Scholar 

  128. Merck. Tramadura effervescent tablets, drops injection [in German]. In: Gelbe Liste Pharmindex. Fulda: Multimedia Medizinische Medien Informations GmbH, 1999: 2205

    Google Scholar 

  129. Richardson J, Bresland K. The management of postsurgical pain in the elderly population. Drugs Aging 1998 Jul; 13: 17–31

    Article  PubMed  CAS  Google Scholar 

  130. Carr DB, Goudas LC. Acute pain. Lancet 1999 Jun 12; 353: 2051–8

    Article  PubMed  CAS  Google Scholar 

  131. Cherny NI. Opioid analgesics: comparative features and prescribing guidelines. Drugs 1996 May; 51: 713–37

    Article  PubMed  CAS  Google Scholar 

  132. Besson J-M. The place of tramadol in the therapy of pain. Drugs 1997; 53 Suppl. 2: 65–6

    Article  Google Scholar 

  133. McQuay H, Moore A, Justins D. Treating acute pain in hospital. BMJ 1997 May 24; 314: 1531–5

    Article  PubMed  CAS  Google Scholar 

  134. Besson J-M, Vickers MD. Tramadol analgesia: synergy in research and therapy. Drugs 1994; 47 Suppl. 1: 1–2

    Article  PubMed  Google Scholar 

  135. Duggan AK. The cost of managing post-operative pain with intravenous tramadol compared with epidural morphine. Br J Med Econ 1995; 9: 37–40

    Google Scholar 

  136. Langford RM. Peri-operative use of tramadol. Int J Pharm Med 1999 Aug; 13: 203–5

    Google Scholar 

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Correspondence to Lesley J. Scott.

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Various sections of the manuscript reviewed by: S.R. Abel, Indiana University Medical Centre, Indianapolis, Indiana, USA; S.S. Bloomfield, University of Cincinnati, Cincinnati, Ohio, USA; J.E. Caldwell, Department of Anesthesia, University of California, San Francisco, California, USA; K.A. Lehmann, Institute of Anaesthesiology and Intensive Care Medicine, University of Cologne, Cologne, Germany; L. Radbruch, Institute of Anaesthesiology and Intensive Care Medicine, University of Cologne, Cologne, Germany; K. Szymanski, Indiana University Medical Centre, Indianapolis, Indiana, USA; P. Tarkkila, Department of Anaesthesia, Helsinki University Centre Hospital, Helsinki, Finland; C.H. Wilder-Smith, Gastrointestinal Unit and Nociception Research Group, Berne, Switzerland.

Data Selection

Sources: Medical literature published in any language since 1993 on tramadol, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘tramadol’ or ‘CG-315’ or ‘CG-315E’ or ‘U-26225A’. Medline search terms were ‘tramadol’. Searches were last updated 26 May 2000.

Selection: Studies in patients with perioperative moderate to severe pain who received tramadol. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Tramadol, analgesia, pain, pharmacodynamics, pharmacokinetics, therapeutic use.

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Scott, L.J., Perry, C.M. Tramadol. Drugs 60, 139–176 (2000). https://doi.org/10.2165/00003495-200060010-00008

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