Drugs

, Volume 53, Supplement 2, pp 18–24

Pharmacologie du tramadol

  • Pierre Dayer
  • Jules Desmeules
  • Laurence Collart
Article

Résumé

Le (±)-tramadol est un analgésique central à faible affinité pour les récepteurs opiacés. Le taux de production de son métabolite M1 (O-déméthyl tramadol), de manière analogue à la codéine, est contrôlé par le polymorphisme génétique de type débrisoquine (CYP2D6) et le dérivé M1 présente, par rapport à la molécule mère, une plus forte affinité pour les récepteurs opiacés. Des données expérimentales et cliniques indiquent que le tramadol exerce aussi son effet antalgique par une action au niveau des voies monoaminergiques centrales. En effet, après administration d’une dose orale unique, le rôle du composant agoniste opioïde μ est mineur dans l’effet antinociceptif du tramadol, la majeure partie de l’antalgie étant attribuable aux propriétés non-opioïdes de la molécule mère. La durée de l’effet analgésique, après administration orale d’une dose unique de 100mg de tramadol, est de l’ordre de 6 heures. L’expérience clinique a confirmé l’efficacité antalgique et la sécurité d’emploi du tramadol qui est approprié pour le traitement de douleurs d’origines variées ne relevant pas du recours aux opioïdes forts.

The Pharmacology of Tramadol

English Abstract

(±)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors.

Its selectivity for μ receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6).

Nevertheless, this affinity for μ receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level.

(±)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+)-Tramadol is a selective agonist of μ receptors and preferentially inhibits serotonin reuptake, whereas (−)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (±)-tramadol.

After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours.

Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse.

Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.

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Références

  1. 1.
    Hennies HH, Friderichs E, Schneider J. Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung 1988; 38: 877–80PubMedGoogle Scholar
  2. 2.
    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: 275–85PubMedGoogle Scholar
  3. 3.
    Raffa RB, Nayak RK, Liao S, et al. The mechanism(s) of action and pharmacokinetics of tramadol hydrochloride. Rev Cont Pharmacother 1995; 6: 485–98Google Scholar
  4. 4.
    Raffa RB. A novel approach to the pharmacology of analgesics. Am J Med 1996; 101 Suppl 1A: 40–6SGoogle Scholar
  5. 5.
    Paar WD, Frankus P, Dengler HJ. The metabolism of tramadol by human liver microsomes. Clin Invest 1992; 70: 708–10CrossRefGoogle Scholar
  6. 6.
    Raffa RB, Vaught JL, Shank RP, et al. Tramadol, a centrally acting analgesic: the contribution of its enantiomers to antinociception and lowered side effects in mice [abstract]. 7th World Congress on Pain: 1993 Aug 22–27: Paris: 521Google Scholar
  7. 7.
    Carlsson KH, Jurna I. Effects of tramadol on motor and sensory responses of the spinal nociceptive system in the rat. Eur J Pharmacol 1987; 139: 1–10PubMedCrossRefGoogle Scholar
  8. 8.
    Mattia A, Vanderah T, Raffa RB, et al. Characterization of the unusual antinociceptive profile of tramadol in mice. Drug Dev Res 1993; 31: 1932–43Google Scholar
  9. 9.
    Kayser V, Besson JM, Guildbaud G. Effects of the analgesic agent tramadol in normal and arthritic rats: comparison with the effects of different opioids, including tolerance and cross-tolerance to morphine. Eur J Pharmacol 1991; 195: 37–45PubMedCrossRefGoogle Scholar
  10. 10.
    Hennies HH, Friderichs E, Wilsman K, et al. Effect of the opioid analgesic tramadol on inactivation of norepinephrine and serotonin. Biochem Pharmacol 1982; 31: 1654–5PubMedCrossRefGoogle Scholar
  11. 11.
    Kayser V, Besson JM, Guildbaud G. Evidence for noradrenergic component in the antinociceptive effect of the analgesic agent tramadol in an animal model of clinical pain, the arthritic rat. Eur J Pharmacol 1992; 224: 83–8PubMedCrossRefGoogle Scholar
  12. 12.
    Collart L, Luthy C, Dayer P. Partial inhibition of tramadol antinociceptive effect by naloxone in man. Proceedings of the British Pharmacological Society, London, September 1992. Br J Clin Pharmacol 1993; 35: 73PGoogle Scholar
  13. 13.
    Collart L, Luthy C, Dayer P. Multimodal analgesic effect of tramadol. Annual Meeting of the American Society of Clinical Pharmacology and Therapeutics, Honolulu, March 1993: Clin Pharmacol Ther 1993; 53: 223Google Scholar
  14. 14.
    Desmeules JA, Piguet V, Collart L, et al. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996; 41: 7–12PubMedCrossRefGoogle Scholar
  15. 15.
    Boiteau R, Tenaillon A, Perrin-Gachadoat D, et al. Haemodynamic and respiratory effects of tramadol and propacetamol in acute exacerbation of chronic heart failure [abstract 832], 7th World Congress on Pain: 1993 Aug 22–27: Paris: 310Google Scholar
  16. 16.
    Canet J, Aguilar JL, Segrí A, et al. Oral ramadol does not depress the respiratory response to CO2 [abstract A294]. Br J Anaesth 1995; 74 Suppl. 1: 90Google Scholar
  17. 17.
    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: 313–40PubMedCrossRefGoogle Scholar
  18. 18.
    Stankov S. Haemodynamic effects of tramadol and morphine in patients with acute myocardial infarction [abstract 780]. 7th World Congress on Pain. 1993 Aug 22–27: Paris: 293Google Scholar
  19. 19.
    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: 567–9PubMedCrossRefGoogle Scholar
  20. 20.
    Wilder-Smith Ch, Bettiga A. Gastrointestinal transit and smooth muscle tone are not affected by the analgesic tramadol. Part 1: helthy volunteers [abstract]. Gastroenterology 1996; 110(4) Suppl.: A780Google Scholar
  21. 21.
    Liao S, Hill JF, Nayak RK. Pharmacokinetics of tramadol following single and multiple oral doses in man [abstract PPDM 8206]. Pharm Res 1992; 9 Suppl. 1: 308Google Scholar
  22. 22.
    Lintz W, Barth H, Osterloh G, et al. The bioavailability of enteral tramadol formulations — 1st communication: capsules. Arzneimittelforschung 1986; 36: 1278–83PubMedGoogle Scholar
  23. 23.
    Gibson TP. Pharmacokinetics, efficacy and safety of analgesia with a focus on tramadol HCl. Am J Med 1996; 101 Suppl 1A: 47–53SGoogle Scholar
  24. 24.
    Lintz W, Beier H, Gerloff J. Absolute bioavailability of tramadol after intramuscular administration of tramal®-50 solution for injection in 12 male volunteers [abstract 1426]. 7th World Congress on Pain: 1993 Aug 22–27: Paris: 537Google Scholar
  25. 25.
    Lintz W, Erlacin S, Frankus E, et al. Metabolismus von Tramadol bei Mensch und Teir. Arzneimittelforschung 1981; 31: 1932–43PubMedGoogle Scholar
  26. 26.
    Leemann T, Dayer P, Meyer UA. Single dose quinidine treatment inhibits metoprolol oxidation in extensive metabolisers. Eur J Clin Pharmacol 1986; 29: 739–41PubMedCrossRefGoogle Scholar
  27. 27.
    Katz WA. Pharmacology and clinical experience with tramadol in osteoarthritis. Drugs 1996; 52 Suppl. 3: 39–47PubMedCrossRefGoogle Scholar
  28. 28.
    Sunshine A. New clinical experience with tramadol. Drugs 1994; 47 Suppl. 1: 8–18PubMedCrossRefGoogle Scholar
  29. 29.
    Piletta P, Porchet HC, Dayer P. Central analgesic effect of acetaminophen but not of aspirin. Clin Pharmacol Ther 1991; 49: 350–354PubMedCrossRefGoogle Scholar
  30. 30.
    Desmeules J, Gascon MP, Dayer P, et al. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991; 41: 23–6PubMedCrossRefGoogle Scholar
  31. 31.
    Brown J, Jackson A, Wan Wagoner D, et al. Tramadol HCl: dose response in pain following caesarean section. Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Orlando, March 1992. Clin Pharmacol Ther 1992; 51: 121CrossRefGoogle Scholar
  32. 32.
    Murphy D, Murphy MB. A comparison of the effects of tramadol and morphine on gastric emptying in man. 18th Annual Meeting of the European Academy of Anaesthesiology: 1996 Aug 29–Sep 1: Copenhagen, Denmark: 31Google Scholar
  33. 33.
    Cossmann M, Wilsman KM. Wirkung und Begleitwirkungen von Tramadol. Therapiewoche 1987; 37: 3475–85Google Scholar
  34. 34.
    Cossmann, Wilsmann KM. Treatment of prolonged pain: assessment of the efficacy and safety of repeated administration of tramadol. Munch Med Wochenschr 1987; 129: 851–4Google Scholar
  35. 35.
    Cossmann M, Wilsmann KM. Anwendung der Tramadol-Injektionslösung (Tramal®) beim akuten Schmerz. Offene Prüfung zur Beurteilung der Akutwirkung und der Verträglichkeit beieinmaliger perenteraler Anwendung. Munch Med Wochenschr 1988; 130: 633–6Google Scholar
  36. 36.
    Radbruch L, Grond S, Lehmann KA. A risk-benefit assessment of tramadol in the management of pain. Drug Saf 1996; 15: 8–29PubMedCrossRefGoogle Scholar
  37. 37.
    Nightingale SL. Important new safety information for tramadol hydrochloride. JAMA 1996; 275(16): 1224PubMedCrossRefGoogle Scholar
  38. 38.
    Riedel F, von Stockhausen HB. Severe cerebral depression after intoxication with tramadol in a 6-month old infant. Eur J Clin Pharmacol 1984; 26: 631–32PubMedCrossRefGoogle Scholar
  39. 39.
    Keup W. Missbrauchmuster bei Abhängigkeit von Alkohol, Medikamenten und Drogen — Frühwarnsystem-Daten für die Bundesrepublik Deutschland 1976–1990. Lambertus Verlag, Freiburg im Breisgau; 1993Google Scholar

Copyright information

© Adis International Limited 1997

Authors and Affiliations

  • Pierre Dayer
    • 1
  • Jules Desmeules
    • 1
  • Laurence Collart
    • 1
  1. 1.Service de Pharmacologie Clinique et Consultation de la DouleurHôpital Cantonal UniversitaireGenève 14Suisse

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