Enhancement of Antinociception but Not Constipation by Combinations

Archives of Medical Research 44 (2013) 495e503 ORIGINAL ARTICLE Enhancement of Antinociception but not Constipation by Combinations Containing Tramadol and Metamizole in Arthritic Rats Francisco Javier Lopez-Mu noz,~ a Luis Alfonso Moreno-Rocha,a Guadalupe Bravo,a Uriah Guevara-Lopez, b Adriana Miriam Domınguez-Ramırez,c and Myrna Deciga-Camposd aDepartamento de Farmacobiologıa, Centro de Investigacion y Estudios Avanzados, Sede Sur, Mexico, D.F., Mexico bDireccion de Educacion e Investigacion en Salud, Unidad Medica de Alta Especialidad Dr. Victorio de la Fuente Narvaez, Instituto Mexicano del Seguro Social, Mexico, D.F., Mexico cDepartamento Sistemas Biologicos, Universidad Autonoma Metropolitana, Unidad Xochimilco, Mexico, D.F., Mexico dSeccion de Posgrado e Investigacion de la Escuela Superior de Medicina del Instituto Politecnico Nacional, Mexico, D.F., Mexico Received for publication February 1, 2013; accepted August 26, 2013 (ARCMED-D-13-00072). Background and Aims. The use of a combination of analgesics could provide an optimal pain treatment with minimal side effects. Combinations of tramadol and some nonsteroidal anti-inflammatory drugs have demonstrated synergistic antinociceptive effects as well as a significantly reduced occurrence of adverse effects. The purpose of this study was to investigate the antinociceptive and constipation effects of tramadol and metamizole alone or in combination in rats and to discern among the types of drug interactions that exist using dose-response curves and an isobolographic analysis. Methods. The antinociceptive effects of tramadol and metamizole, alone or in various combination ratios, were quantitatively evaluated using the ‘‘pain-induced functional impairment model in the rat.’’ Additionally, the constipation effect was evaluated using the charcoal meal test. Results. Tramadol (3.2e56.2 mg/kg) and metamizole (56.2e562.3 mg/kg) demonstrated a dose-dependent response with tramadol being more efficacious and potent than metamizole. Twenty-five different combinations of tramadol with metamizole were analyzed, and the evaluated combinations exhibited antinociceptive effects that were either additive or potentiative. An optimal combination was established with 3.2 mg/kg of tramadol and 316.2 mg/kg of metamizole. However, the constipation observed with this combination was more severe than that observed with the administration of tramadol alone. Our results reveal a possible interaction between the two drugs, which may be pharmacokinetic and/ or pharmacodynamic in nature. Conclusions. The preclinical antinociceptive interaction and adverse effects produced by the combination of tramadol and metamizole suggests that caution should be exercised when using this combination in the clinical therapy of pain. Ó 2013 IMSS. Published by Elsevier Inc. Key Words: Antinociception, Synergism, Constipation, Tramadol, Metamizole, PIFIR model. Introduction using combination therapy is that, in some cases, the antinociceptive effects can be improved while the adverse effects Different combinations of opioid and nonsteroidal anti- can be minimized. This postulate refers to the fact that inflammatory drugs (NSAIDs) are commonly used to con- improving antinociceptive effectiveness due to antinocicep- trol various pain statements (1). The potential advantage of tive synergism should enable a reduction in dosage and consequently a significant decrease in the incidence of ~ Address reprint requests to: Francisco Javier Lopez-Munoz, Departa- adverse effects (2). Previous studies with morphine and mento de Farmacobiologıa, Centro de Investigacion y Estudios Avanzados, Sede Sur, Calzada de los Tenorios 235, Colonia Granjas Coapa, Mexico, metamizole (3) found an enhanced antinociceptive effect, D.F., C.P. 14330, Mexico; Phone: (þ52) (55) 5483-2851; FAX: (þ52) thus confirming the positive interaction between these two (55) 5483-2863; E-mail: fl[email protected] or fl[email protected] drugs. The analgesic efficacy of tramadol, which is a weak 0188-4409/$ - see front matter. Copyright Ó 2013 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2013.09.004 496 Lopez-Mu noz~ et al./ Archives of Medical Research 44 (2013) 495e503 opioid-agonist with analgesic properties, is the result of a (Mexico City, Mexico), respectively. Uric acid was pur- complex interaction between opioid receptors with adren- chased from the Sigma Chemical Co. (St. Louis, MO) and ergic (4) and serotonergic systems (5). The combination of suspended in mineral oil. Either tramadol or metamizole tramadol with several NSAIDs, such as acetylsalicylic acid was administered subcutaneously (s.c.) using an isotonic (6), paracetamol (7), ibuprofen (8), naproxen (9), piroxicam saline solution as the vehicle (0.9% w/v). The drugs were (10) and ketorolac (2) has shown a positive interaction in freshly prepared and administered at a volume of 2 mL/kg terms of its antinociceptive effects in a dose-dependent body weight for tramadol or metamizole. The doses manner. However, the combination of tramadol with rofe- mentioned in the text refer to the salts of these substances. coxib antagonized the antinociceptive effect of tramadol (11). Recently we demonstrated that, upon repeated admin- Measurement of Antinociceptive Activity istration, the positive synergistic antinociceptive effect of The antinociceptive activity was assessed using the PIFIR the combination of tramadol and metamizole generated anti- model, which has previously been described in detail nociceptive tolerance (12). Currently, there is little preclini- (13). The animals were lightly anesthetized with ethylic cal and quantitative evidence to establish the antinociceptive ether in an anesthesia chamber, and nociception was interaction of this particular combination of tramadol and induced by an intra-articular (i.a.) injection of 0.05 mL of metamizole. Consequently, the purpose of this study was 30% uric acid suspended in mineral oil in the knee joint to investigate the antinociceptive effects of tramadol and of the right hind limb. The intra-articular injection was per- metamizole, alone or in combination, using the ‘‘pain- formed through the patellar ligament using a 1 mL glass sy- induced functional impairment model in the rat (PIFIR ringe with a 24 gauge needle, 5 mm in length. Immediately model) (13) and the isobolographic analysis (14). The isobo- following this injection, an electrode was attached to the lographic method enables the discernment of the types of plantar surface of each hind paw (right and left) between interactions that are present and the classification of these ef- the plantar pads. The rats were then allowed to recover fects as potentiation, addition or sub-addition. Additionally, from anesthesia and placed on a 30-in diameter stainless the constipating effects produced by these drugs adminis- steel cylinder. The cylinder was rotated at 4 rpm, forcing tered alone or in combination were analyzed. the rats to walk. The variable to be measured was the time of contact between each hind paw and the cylinder. When the electrode placed on the animal’s paw made contact with Materials and Methods the cylinder floor, a circuit was closed, and the time the cir- Animals cuit remained closed was recorded. The cylinder was rotated for 2-min periods, during which the recordings were Male Wistar rats (Crl [WI]fBR) weighing 180e200 g from made; 28-min rest periods were interspersed between the the production unit of the laboratory of animal species of recordings. Following uric acid injection, the animals the Metropolitan Autonomous University were used. Ani- developed a progressive dysfunction of the injured limb. mals were housed in an acclimatized room (22 Æ 2 C) under The time of contact of the injured hind limb reached a zero a light-dark cycle of 12 h (lights on at 7:00), and experiments value 2.5 h after the uric acid injection. In all subsequent were performed during the light phase of the cycle. The experiments, treatments were administered 2.5 h after the experimental protocol (no. 0444-08) was approved by the uric acid injection. Thus, this time was considered to be local Institutional Animal Care and Use Committee in accor- time zero for the measurement of the antinociceptive effect, dance with the Mexican Federal Regulations for the Care and drugs were administered at this time. The time of con- and Use of Laboratory Animals NOM-062-ZOO-1999 tact was measured every 28 min for up to 4 h after drug (Mexican Ministry of Health). The protocol followed the administration. The data are expressed as a percentage of Guidelines on Ethical Standards for the investigation of the functionality index (FI%), i.e., the time of contact of Experimental Pain in Animals (15) and the Committee for the injected paw divided by the time of contact of the Research and Ethical Issues of the International Association control left paw x100. The recovery of the FI% was for the Study of Pain (16). At least 8 h before the experiment considered to be an expression of the antinociceptive effect. began, the rats were subjected to fasting with free access to Time-response curves were plotted to detect the onset of the drinking water. The number of animals used was kept to a antinociceptive effect, as were dose-response curves to minimum and the conditions were controlled. Each animal determine the antinociceptive efficacies and potency. All was used only once and, at the end of the study, the rats were experiments were performed between 7:00 and 14:00 h. euthanized in CO2 to avoid unnecessary

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