Cirugía y Cirujanos

Contents by Year, Volume and Issue

Table of Contents

General Information

Instructions for Authors

Message to Editor

Editorial Board

>Journals >Cirugía y Cirujanos >Year 2007, Issue 5

Godínez-Chaparro B, Guevara-López U, de la O-Arciniega M, Cortés-Arroyo AR, López-Muñoz FJ
Antinociceptive effects of the combination metamizol + morphine in rats with intense pain (arthritic gout-type pain produced with AU)
Cir Cir 2007; 75 (5)

Language: Español
References: 41
Page: 371-376
PDF: 76.98 Kb.

[Full text - PDF]


Background: The antinociceptive effects of metamizol and morphine administered either separately or in combination were determined in the “Pain-Induced Functional Impairment Model in the Rat” (PIFIR antinociceptive model).
Methods: Intense nociception (or intense pain) was induced by the intra-articular injection of uric acid (50 %) in the right hind limb inducing its dysfunction. Animals then received analgesic agents, and the recovery of functionality over time was assessed as an expression of antinociception.
Results: Metamizol (177.8 mg/kg SC) or morphine (3.2 mg/kg SC) separately resulted in a lower antinociceptive effect (22.1 ± 5.4 area units [au] and 31.8 ± 9.4 au, respectively). Moreover, the combination of metamizol (177.8 mg/kg) with morphine (3.2 mg/kg) resulted in a potentiation (293.7 ± 16.6 au). The antinociceptive effect observed using the combination was significantly greater than expected on the basis of addition of the individual effects. The percent change in antinociceptive effects, using the combination, was 444.9 %.
Conclusions: This represents the first study to show that metamizol + morphine can produce potentiation of their antinociceptive effects in intense pain.

Key words: Analgesia, antinociception, morphine, metamizol, synergism.


  1. 1. López-Muñoz FJ, Castañeda-Hernández G, Villalón CM, Terrón JA, Salazar LA. Analgesic effects of combinations containing opioid drugs with either aspirin or acetaminophen in the rat. Drug Dev Res 1993;29:299-304.

  2. 2. López-Muñoz FJ, Villalón CM, Terrón JA, Salazar LA. Analgesic interactions produced by dipyrone and either morphine or D-propoxyphene in the Pain-Induced Functional Impairment Model in Rat. Drug Dev Res 1994;32:50-57.

  3. 3. López-Muñoz FJ, Villalón CM, Terrón JA, Salazar LA. Analgesic interactions produced by combinations of dipyrone and morphine in the rat. Proc West Pharmacol Soc 1994;37:17-19.

  4. 4. López-Muñoz FJ, Villalón CM, Terrón JA, Salazar LA. Doses of acetyl salicylic acid and morphine in combination which provided either maximal levels of analgesia or the highest potentiation effect in the rat. Drug Dev Res 1995;35:94-101.

  5. 5. Raffa RB. Pharmacology of oral combination analgesics: rational therapy for pain. J Clin Pharm Ther 2001;26:257-264.

  6. 6. Hernández-Delgadillo GP, Cruz SL. Dipyrone potentiates morphine-induced antinociception in dipyrone-treated and morphine-tolerant rats. Eur J Pharmacol 2004;502:67-73.

  7. 7. López-Muñoz FJ, Díaz-Reval MI, Terón JA, Déciga-Campos M. Analysis of the analgesic interactions between ketorolac (NSAID) and tramadol (atypical opioid drug) during arthritic nociception in rat. Eur J Pharmacol 2004;484:157-165.

  8. 8. Gilron I, Max M. Combination pharmacotherapy for neuropathic pain: current evidence and future directions. Expert Rev Neurother 2005;5:823-830.

  9. 9. Domínguez-Ramírez AM, Hernández-Delgadillo GP, Ventura R, Díaz IM, López-Muñoz FJ. Analgesic efficacy of the combination metamizol + morphine after subchronic treatment in rats. Drug Dev Res 2000;51:260-267.

  10. 10. Ergün H, Frattarelli DAC, Aranda JV. Characterization of the role of physicochemical factors on the hydrolysis of dipyrone. J Pharm Biomed Anal 2004;35:479-487.

  11. 11. Arcila-Herrera H, Barragán-Padilla S, Borbolla-Escoboza JR, et al. Consenso de un grupo de expertos mexicanos. Eficacia y seguridad del metamizol (dipirona). Gac Med Mex 2004;140:99-101.

  12. 12. Doretto MC, García-Cairasco N, Pimenta NJG, Souza DA, Tatsuo MAKF. Dipyrone, a novel anticonvulsant agent? Insights from three experimental epilepsy models. Neuro Report 1998;9:2415-2421.

  13. 13. Ergün H, Uzbay IT, Celik T, Kayir H, Yesukyurt Ö, Tulunay FC. Dipyrone inhibits ethanol withdrawal and pentylenetetrazol-induced seizures in rats. Drug Dev Res 2001;53:254-259.

  14. 14. Reis GML, Doretto MC, Duarte IDG, Tatsuo MAKF. Do endogenous opioids and nitric oxide participate in the anticonvulsant action of dipyrone? Braz J Med Biol Res 2003;36:1263-1268.

  15. 15. Hernández-Delgadillo GP, Ventura R, Díaz I, Domínguez AM, López-Muñoz FJ. Metamizol potentiates morphine antinociception but not constipation after chronic treatment. Eur J Pharmacol 2002;441:177-183.

  16. 16. Hernández-Delgadillo GP, López-Muñoz FJ, Salazar LA, Cruz SL. Morphine and dipyrone co-administration delays tolerance development and potentiates antinociception. Eur J Pharmacol 2003;469:71-79.

  17. 17. López-Muñoz FJ, Salazar LA, Castañeda-Hernández G, Villarreal JE. A new model to assess analgesic activity: pain-induced functional impairment in the rat (PIFIR). Drug Dev Res 1993;28:169-175.

  18. 18. Covino BG, Dubner R, Gybels J, et al. Ethical standards for investigation of experimental pain in animals. Pain 1980;9:141-143.

  19. 19. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109-110.

  20. 20. López-Muñoz FJ. “Análisis de algunos factores que determinan la farmacodinamia de agentes analgésicos”. Tesis para obtener el grado de maestro en Ciencias, Departamento de Farmacología y Toxicología del Cinvestav, Mexico, 1986.

  21. 21. Malmberg AB, Yaksh TL. Pharmacology of the spinal action of ketorolac, morphine, ST-91, U50488H, and L-PIA on the formalin test and an isobolographic analysis of the NSAID interaction. Anesthesiology 1993;79:270-281.

  22. 22. Maves TJ, Pechman PS, Meller ST, Gebhart GF. Ketorolac potentiates morphine antinociception during visceral nociception in the rat. Anesthesiology 1994;80:1094-1101.

  23. 23. Calimlim JF, Wardell WM, Davis HT, Lasagna L, Gillies AJ. Analgesic efficacy of an orally administered combination of pentazocine and aspirin. Clin Pharmacol Ther 1976;21:34-43.

  24. 24. Bentley KC, Head TW. The additive analgesic efficacy of acetaminophen, 1000 mg, and codeine, 60 mg, in dental pain. Clin Pharmacol Ther 1987;42:634-640.

  25. 25. Picard P, Bazin JE, Conio N, Ruiz F, Schoeffler P. Ketorolac potentiates morphine in postoperative patient-controlled analgesia. Pain 1997;73:401-406.

  26. 26. Martin WR. Pharmacology of opioids. Pharmacol Rev 1984;35:283–323.

  27. 27. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Rall TW, Nies AS, Taylor P, eds. Goodman and Gilmans’s The Pharmacological Basis of Therapeutics, 8th ed. Elmsford, NY: Pergamon Press;1990. pp. 485–521.

  28. 28. Lipp J. Possible mechanism of morphine analgesia. Clin Neuropharmacol 1991;14:131–147.

  29. 29. Yaksh TL. Direct evidence that spinal serotonin and noradrenalin terminals mediate the spinal antinociceptive effects of morphine in the periaqueductal gray. Brain Res 1979;160:180–185.

  30. 30. Yeomans DC, Clark FM, Paice JA, Proudfit HK. Antinociception induced by electrical stimulation of spinally projecting noradrenergic neurons in the catecholamine cell group of the rat. Pain 1992;48:449–461.

  31. 31. Kawamata M, Omote K, Namiki A, Ishitani K. Contribution of descending inhibitory and spinal cholinergic systems to visceral antinociception of morphine. Anaesthesiology 1993;79:A701.

  32. 32. Lorenzetti BB, Ferreira SH. The analgesic effect of quaternary analogues of morphine and nalorphine. Braz J Med Biol Res 1982;15:285.

  33. 33. Lorenzetti BB, Ferreira SH. Mode of analgesic action of dipyrone: direct antagonism of inflammatory hyperalgesia. Eur J Pharacol 1985;114:375-381.

  34. 34. Lim KS, Guzman F, Rodgers DW, et al. Site of action of narcotic and non-narcotic analgesics determined by blocking bradykinin-evoked visceral pain. Arch Int Pharmacodyn Ther 1964;152:25-58.

  35. 35. Ferreira SH. Prostaglandins, aspirin-like drugs and analgesia. Nature 1972;240: 200-239.

  36. 36. Campos C, de Gregorio R, García-Nieto R, Gago F, Ortiz P, Alemany S. Regulation of cyclooxigenase activity by metamizol. Eur J Pharmacol 1999;378:339-347.

  37. 37. Shimada SG, Otterness IG, Stitt JT. A study of the mechanism of action of the mild analgesic dipyrone. Agents Actions 1994;4:188-192.

  38. 38. Duarte ID, Santos IR, Lorenzetti BB, Ferreira SH. Analgesia by direct antagonism of nociceptor sensitization involves the arginine-nitric oxide c-GMP pathway. Eur J Pharmacol 1992;217:225-227.

  39. 39. Tortorici V, Vázquez E, Vanegas H. Naloxone partial reversal of the antinociception produced by dipyrone microinjected into periaqueductal gray of rats: possible involvement of medullary off- and on-cells. Brain Res 1996;725:106-110.

  40. 40. Vlaskovska M, Surcheva S, Ovcharov R. Importance of endogenous opioids and prostaglandins in the action of analgin (metamizole) and verapamil. Farmakol Toksikol 1989;52:25-29.

  41. 41. Beirith A, Santos ARS, Rodrigues AL, Creczynski-Pasa TB, Calixto JB. Spinal and supraspinal antinociceptive action of dipyrone in formalin, capsaicin and glutamate tests: study of the mechanism of action. Eur J Pharmacol 1998;345:233-245.

>Journals >Cirugía y Cirujanos >Year 2007, Issue 5

· Journal Index 
· Links 
Copyright 2010