Synergism between tramadol and meloxicam in the formalin test involves both opioidergic and serotonergic pathways

Authors

  • Mario A. Isiordia-Espinoza,

    1. Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, México, D.F., 11340 México
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  • Flavio Terán-Rosales,

    1. Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, México, D.F., 11340 México
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  • Gerardo Reyes-García,

    1. Sección de Estudios de Postgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, México, D.F., 11340 México
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  • Vinicio Granados-Soto

    Corresponding author
    1. Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur. México, D.F., 14330 México
    • Departamento de Farmacobiología, Cinvestav, Sede Sur, Calzada Tenorios 235, Col. Granjas Coapa, D.F., 14330 México
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Abstract

This study was designed to evaluate the antinociceptive interaction of the tramadol–meloxicam combination in different proportions (tramadol + meloxicam in 1:1, 1:3, and 3:1 ratios), as well as the role of nitric oxide, opioidergic, and serotonergic pathways in the antinociceptive effect of the combination. The effects of individual drugs and fixed-ratio combinations were assayed using the 3% formalin test in mice. Isobolographic analysis was employed to characterize the synergism produced by the combinations. Tramadol (3.16–10 mg/kg, i.m.), meloxicam (3.16–17.8 mg/kg, i.m.), and tramadol–meloxicam combinations produced a dose-dependent antinociceptive effect. ED30 values were estimated for the individual drugs, and isobolograms were constructed. The tramadol + meloxicam 1:1 and 1:3 ratio combinations showed synergistic interactions while the 3:1 ratio produced additive effects. Naloxone (1 mg/kg, i.m.) or methiothepin (0.1 mg/kg, i.m.), but not L-NAME (3 mg/kg, i.m.), prevented the antinociceptive effects of the combination. These data suggest that (1) the tramadol–meloxicam combination produces a functional synergistic interaction that involves both opioid and serotonin receptors, and (2) this combination may be a promising tool in pain management. Drug Dev Res 73: 43–50, 2012. © 2011 Wiley Periodicals, Inc.

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