Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Pharmacology 2007;79:214–222 DOI: 10.1159/000101390 Isobolographic Analyses of the Gabapentin- Metamizol Combination after Local Peripheral, Intrathecal and Oral Administration in the Rat Luis F. Ortega-Varela a, b Jorge E. Herrera a Nadia L. Caram-Salas c Héctor I. Rocha-González c Vinicio Granados-Soto c, d a Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, México, D.F.; b Escuela Preparatoria Melchor Ocampo, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán; c Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados, Sede Sur, México, D.F., and d Centro de Investigación y de Estudios Avanzados, Unidad Monterrey, Monterrey, N.L., Mexico ergism. Data confirm that low doses of the gabapentin and metamizol can interact synergistically to reduce formalin- induced nociceptive behavior suggesting that this combina- tion could be useful to treat inflammatory pain in humans. Copyright © 2007 S. Karger AG, Basel Introduction Currently, combination therapy is commonly used in an attempt to improve pain management. The potential advantage of using combination therapy is that analgesic effects can be maximized while the incidence of adverse side effects could be minimized. Moreover, the multiplic- ity of mechanisms involved in pain [1] suggests that com- bination therapy can improve pain management [2]. In addition to the inhibitory action on the prostaglan- din synthesis [3, 4], it has been reported that certain non- steroidal anti-inflammatory drugs (NSAIDs) are able to produce part of their antinociceptive effect through the activation of the nitric oxide-cyclic GMP pathway [5–8] . A prototype drug for these effects is metamizol (dipy- rone). There is evidence to support that metamizol pro- duces its antinociceptive effect through inhibition of prostaglandin synthesis in both the peripheral and cen- Key Words Antinociception  Synergy  Isobolograms  Gabapentin  Metamizol  Formalin test Abstract This study was designed to evaluate the possible antinoci- ceptive interaction between gabapentin and metamizol on formalin-induced nociception. Gabapentin, metamizol or a fixed dose-ratio combination of both drugs were assessed after local peripheral, intrathecal and oral administration in rats. Isobolographic analyses were employed to define the nature of the interaction between drugs. Gabapentin, met- amizol and gabapentin-metamizol combinations yielded a dose-dependent antinociceptive effect when administered by the three different routes. ED 30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED 30 values for the combination estimated from the isobolograms were 21.11 8 1.17  g/paw, 104.6 8 5.5  g/rat and 78.8 8 5.5 mg/kg for the local peripheral, intra- thecal and oral administration routes, respectively. These values were significantly higher than the experimentally ob- tained ED 30 values which were 11.3 8 1.5  g/paw, 36.8 8 3.1  g/rat and 15 8 1.2 mg/kg indicating a synergistic inter- action. Systemic administration resulted in the highest syn- Received: August 24, 2006 Accepted: December 22, 2006 Published online: March 29, 2007 Vinicio Granados-Soto, PhD Departamento de Farmacobiología, Cinvestav, Sede Sur Calzada de los Tenorios 235, Col. Granjas Coapa 14330 México, D.F. (Mexico) Tel. +52 55 5061 2868, Fax +52 55 5061 2863, E-Mail vgranados@prodigy.net.mx © 2007 S. Karger AG, Basel 0031–7012/07/0794–0214$23.50/0 Accessible online at: www.karger.com/pha