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Synergism Between Fentanyl and Tramadol in Tonic Inflammatory Pain: the Orofacial Formalin Test

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Abstract

Opioids have been used for long time to management of pain, the coadministration of two opioids may induce synergism. The present study was conducted to determine the antinociceptive interaction between the dual mechanism of action of tramadol compared to the main of fentanyl antinociception in the orofacial formalin which represents a model of persistent cutaneous nociception in the region innervated by the trigeminal nerve. The i.p. administration of tramadol and fentanyl induced a dose-dependent antinociception with an ED50 of 2.97 ± 0.32 mg/kg for phase I and 1.79 ± 0.30 mg/kg for phase II and 0.062 ± 0.0040 mg/kg in phase I and 0.041 ± 0.0039 mg/kg in phase II, respectively. The coadministration of fentanyl with tramadol induced synergism in both phases of the test with an interaction index of 0.343 and 0.163 for phase I and phase II, respectively. This finding could be explained by the more complex pharmacology of tramadol compared to fentanyl.

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REFERENCES

  1. Waldhoer, M., S.E. Bartlett, and J.L. Whistler. 2004. Opioid receptors. Annual Review of Biochemistry 73: 953–990.

    Article  PubMed  CAS  Google Scholar 

  2. Trescot, A.M., S. Datta, M. Lee, and H. Hansen. 2008. Opioid pharmacology. Pain Physician 11: S133–S153.

    PubMed  Google Scholar 

  3. Raffa, R.B., and D.J. Stone. 2008. Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice. The Journal of Pharmacology and Experimental Therapeutics 303: 557–562.

    Google Scholar 

  4. Kelly, S., K.S. Lewis, and N.H. Han. 1997. Tramadol: a new centrally acting analgesic. American Journal of Health-System Pharmacy 54: 643–652.

    Google Scholar 

  5. Curatolo, M., and G. Sveticic. 2002. Drug combination in pain treatment: a review of the published evidence and a method for finding the optimal combination. Best Practice & Research Clinical Anaesthesiology 216: 507–512.

    Article  Google Scholar 

  6. Smith, H.S. 2008. Combination opioids analgesics. Pain Physician 11: 202–214.

    Google Scholar 

  7. Stein, C., J.D. Clark, U. Oh, M.R. Vasko, G.L. Wilcox, A.C. Overland, T.W. Vanderah, and R.H. Spencer. 2009. Peripheral mechanisms of pain and analgesia. Brain Research Reviews 60: 90–113.

    Article  PubMed  CAS  Google Scholar 

  8. Luccarini, P., A. Childeric, A.M. Gayder, D. Voisin, and R. Dallel. 2006. The orofacial formalin test in the mouse: a behavioral model for studying physiology and modulation of trigeminal nociception. The Journal of Pain 7: 908–914.

    Article  PubMed  Google Scholar 

  9. Miranda, H.F., F. Sierralta, and J.C. Prieto. 2009. Synergism between NSAIDs in the orofacial formalin test in mice. Pharmacology, Biochemistry, and Behavior 92: 314–318.

    Article  PubMed  CAS  Google Scholar 

  10. Tallarida, R.J. 2000. Drug synergism and dose-effect data analysis. Boca Ratón: Chapman & Hall/CRC Press. p. 26-131.

  11. Dubuisson, D., and S.G. Dennis. 1977. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4: 161–174.

    Article  PubMed  CAS  Google Scholar 

  12. Tjølsen, A., O.-G. Berge, S. Hunskaar, J.H. Rosland, and K. Hole. 1992. The formalin test: an evaluation of the method. Pain 51: 5–17.

    Article  PubMed  Google Scholar 

  13. Sessle, B.J. 2005. Peripheral and central mechanisms of orofacial pain and their clinical correlates. Minerva Anesthesiology 71: 117–136.

    CAS  Google Scholar 

  14. Bolan, E.A., R.J. Tallarida, and G.W. Pasternak. 2002. Synergy between mu opioid ligands, evidence for functional interactions among mu opioid receptor subtypes. The Journal of Pharmacology and Experimental Therapeutics 303: 557–562.

    Article  PubMed  CAS  Google Scholar 

  15. Pan, Y.X., J. Xu, H.S. Moskowitz, M. Xu, and G.W. Pasternak. 2005. Identification of four novel exon 5 splice variants of the mouse μ- opioid receptor gene: Functional consequences of C-terminal splicing. Molecular Pharmacology 68: 866–875.

    PubMed  CAS  Google Scholar 

  16. Munro, G., C.A. Baek, H.K. Erichsen, A.N. Nielsen, E.Ø. Nielsen, J. Scheel-Kruger, P. Weikop, and D. Peters. 2008. The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3- yl]-propan-1- one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol. Neuropharmacology 54: 331–343.

    Article  PubMed  CAS  Google Scholar 

  17. Ozdogan, U.K., and M.S. Lahdesmaki. 2006. The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the α2A-adrenoceptor gene. European Journal of Pharmacology 529: 105–113.

    Article  PubMed  Google Scholar 

  18. Gercek, A., Z. Eti, F.Y. Gogus, and A. Sav. 2004. The analgesic and antiinflammatory effects of subcutaneous bupivacaine, morphine and tramadol in rats. Agriculture 16: 53–58.

    Google Scholar 

  19. Miranda, H.F., M.M. Puig, M.A. Romero, and J.C. Prieto. 2009. Effects of tramadol and dexketoprofen on analgesia and gastrointestinal transit in mice. Fundamental and Clinical Pharmacology 23: 81–88.

    Article  PubMed  CAS  Google Scholar 

  20. Romero, A., H.F. Miranda, and M.M. Puig. 2010. Antinociceptive effects of morphine, fentanyl, tramadol and their combination in morphine-tolerant mice. Pharmacology, Biochemistry, and Behavior 97: 363–369.

    Article  PubMed  CAS  Google Scholar 

  21. Romero, A., H.F. Miranda, and M.M. Puig. 2010. Analysis of the opioide–opioid combinations according to the nociceptive stimulus in mice. Pharmacological Research 61: 511–518.

    Article  PubMed  CAS  Google Scholar 

  22. Sirohi, S., S.V. Dighe, E.A. Walker, and B.C. Yoburn. 2008. The analgesic efficacy of fentanyl: Relationship to tolerance and μ-opioid receptor regulation. Pharmacology, Biochemistry, and Behavior 91: 115–120.

    Article  PubMed  CAS  Google Scholar 

  23. Barrera, N.P., B. Morales, S. Torres, and M. Villalon. 2005. Principles: Mechanisms and modelling of synergism in cellular responses. Trends in Pharmacological Sciences 26: 526–532.

    Article  PubMed  CAS  Google Scholar 

  24. Kenakin, T. 2007. Collateral efficacy in drug discovery: Taking advantage of the good (allosteric) nature of 7TM receptors. Trends in Pharmacological Sciences 28: 407–415.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS

This work was partially supported by project DI-02-11/CB from Universidad Andrés Bello. The expert technical assistance of Jose Lopez and Alejandro Correa is gratefully recognized.

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Authors and Affiliations

  1. Pharmacology Program, School of Medicine, ICBM, Faculty of Medicine, Universidad de Chile, Independencia 1027, Santiago, 7, Chile

    Hugo F. Miranda, Ramiro J. Zepeda, Fernando Sierralta & Juan C. Prieto

  2. Faculty of Medicine, School of Pharmacy, Universidad Andrés Bello, Santiago, Chile

    Hugo F. Miranda & Viviana Noriega

  3. Cardiovascular Department, Hospital Clínico, Universidad de Chile, Santiago, Chile

    Juan C. Prieto

Authors
  1. Hugo F. Miranda
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  2. Viviana Noriega
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  3. Ramiro J. Zepeda
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  4. Fernando Sierralta
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  5. Juan C. Prieto
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Correspondence to Hugo F. Miranda.

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Miranda, H.F., Noriega, V., Zepeda, R.J. et al. Synergism Between Fentanyl and Tramadol in Tonic Inflammatory Pain: the Orofacial Formalin Test. Inflammation 35, 1132–1137 (2012). https://doi.org/10.1007/s10753-011-9420-7

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