Drugs in R & D

, Volume 8, Issue 1, pp 51–57 | Cite as

Tramadol has a Better Potency Ratio Relative to Morphine in Neuropathic than in Nociceptive Pain Models

  • Thomas Christoph
  • Babette Kögel
  • Wolfgang Strassburger
  • Stephan A. Schug
Original Research Article

Abstract

Background and objective: Treatment of neuropathic pain remains a challenge and the role of various analgesics in this setting is still debated. The effects of tramadol, an atypically acting analgesic with a combined opioid and monoaminergic mechanism of action, and morphine, a prototypical opioid, were tested in rat models of neuropathic and nociceptive pain.

Methods: Cold allodynia and mechanical hypersensitivity, symptoms of neuropathic pain, were studied in rat models of mononeuropathic pain. Cold allodynia was analyzed in the chronic constriction injury (CCI) model and mechanical hypersensitivity was analyzed in the spinal nerve ligation (SNL) model. Heat-induced rat tail-flick latencies were determined as measure for nociceptive pain.

Results: Cold allodynia and mechanical hypersensitivity were strongly attenuated with similar absolute potency after intravenous administration of tramadol and morphine. The doses of drug that were calculated to result in 50% pain inhibition (ED50) for tramadol and morphine were 2.1 and 0.9 mg/kg, respectively, in CCI rats and 4.3 and 3.7 mg/kg, respectively, in SNL rats. In the tail-flick assay of acute nociception, the potency of the two drugs differed markedly, as seen by ED50 values of 5.5 and 0.7 mg/kg intravenously for tramadol and morphine, respectively. Accordingly, the analgesic potency ratio (ED50 tramadol/ED50 morphine) of both compounds differed in neuropathic (potency ratio 2.3 in CCI and 1.2 in SNL) and nociceptive pain models (potency ratio 7.8), suggesting a relative increase in potency of tramadol in neuropathic pain compared with nociceptive pain.

Conclusion: The results of this study are consistent with clinical data supporting the efficacy of opioids in neuropathic pain conditions, and furthermore suggest an additional contribution of the monoaminergic mechanism of tramadol in the treatment of neuropathic pain states.

References

  1. 1.
    Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988; 33: 11–23PubMedCrossRefGoogle Scholar
  2. 2.
    Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology 1991; 41: 1024–8PubMedCrossRefGoogle Scholar
  3. 3.
    Dubner R. A call for more science, not more rhetoric, regarding opioids and neuropathic pain. Pain 1991; 47: 1–2PubMedCrossRefGoogle Scholar
  4. 4.
    Dellemijn PL, Vanneste JA. Randomised double-blind active-placebo-controlled crossover trial of intravenous fentanyl in neuropathic pain. Lancet 1997; 349: 753–8PubMedCrossRefGoogle Scholar
  5. 5.
    Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003; 60: 927–34PubMedCrossRefGoogle Scholar
  6. 6.
    Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998; 50: 1837–41PubMedCrossRefGoogle Scholar
  7. 7.
    Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83: 389–400PubMedCrossRefGoogle Scholar
  8. 8.
    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
  9. 9.
    Collins SL, Moore RA, McQuay HJ, et al. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000; 20: 449–58PubMedCrossRefGoogle Scholar
  10. 10.
    Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33: 87–107PubMedCrossRefGoogle Scholar
  11. 11.
    Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355–63PubMedCrossRefGoogle Scholar
  12. 12.
    Apaydin S, Uyar M, Karabay NU, et al. The anti-nociceptive effect of tramadol on a model of neuropathic pain in rats. Life Sci 2000; 66: 1627–37PubMedCrossRefGoogle Scholar
  13. 13.
    Iyengar S, Webster AA, Hemrick-Luecke SK, et al. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J Pharmacol Exp Ther 2004; 311: 576–84PubMedCrossRefGoogle Scholar
  14. 14.
    Martin TJ, Hairston CT, Lutz PO, et al. Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain. Eur J Pharmacol 1998; 357: 25–32PubMedCrossRefGoogle Scholar
  15. 15.
    Ossipov MH, Lopez Y, Bian D, et al. Synergistic anti-nociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 1997; 86: 196–204PubMedCrossRefGoogle Scholar
  16. 16.
    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: 335–40PubMedCrossRefGoogle Scholar
  17. 17.
    Suzuki R, Chapman V, Dickenson AH. The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain. Pain 1999; 80: 215–28PubMedCrossRefGoogle Scholar
  18. 18.
    Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983; 16: 109–10PubMedCrossRefGoogle Scholar
  19. 19.
    Christoph T, Kogel B, Schiene K, et al. Broad analgesic profile of buprenorphine in rodent models of acute and chronic pain. Eur J Pharmacol 2005; 507: 87–98PubMedCrossRefGoogle Scholar
  20. 20.
    D’Amour FE, Smith DL. A method for determining loss of pain sensation. J Pharmacol Exp Ther 1941; 72: 74–8Google Scholar
  21. 21.
    Rashid MH, Inoue M, Toda K, et al. Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain. J Pharmacol Exp Ther 2004; 309: 380–7PubMedCrossRefGoogle Scholar
  22. 22.
    Mico JA, Ardid D, Berrocoso E, et al. Antidepressants and pain. Trends Pharmacol Sci 2006; 27: 348–54PubMedCrossRefGoogle Scholar
  23. 23.
    Esser MJ, Sawynok J. Acute amitriptyline in a rat model of neuropathic pain: differential symptom and route effects. Pain 1999; 80: 643–53PubMedCrossRefGoogle Scholar
  24. 24.
    Godefroy F, Butler SH, Weil-Fugazza J, et al. Do acute or chronic tricyclic antidepressants modify morphine anti-nociception in arthritic rats? Pain 1986; 25: 233–44PubMedCrossRefGoogle Scholar
  25. 25.
    Duhmke RM, Cornblath DD, Hollingshead JR. Tramadol for neuropathic pain. Cochrane Database Syst Rev 2004; (2): CD003726Google Scholar
  26. 26.
    Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999; 83: 85–90PubMedCrossRefGoogle Scholar
  27. 27.
    Raffa RB, Friderichs E. The basic science aspect of tramadol hydrochloride. Pain Reviews 1996; 3: 249–71Google Scholar
  28. 28.
    Vickers MD, Paravicini D. Comparison of tramadol with morphine for post-operative pain following abdominal surgery. Eur J Anaesthesiol 1995; 12: 265–71PubMedGoogle Scholar
  29. 29.
    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: 646–54PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Thomas Christoph
    • 1
  • Babette Kögel
    • 1
  • Wolfgang Strassburger
    • 1
  • Stephan A. Schug
    • 2
  1. 1.Biomedical ResearchGrünenthal GmbHAachenGermany
  2. 2.Pharmacology and Anaesthesiology Unit, School of Medicine and PharmacologyUniversity of Western AustraliaPerthAustralia

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