Enhancement of antinociception but not constipation by combinations containing tramadol and metamizole in arthritic rats.
OBJECTIVE
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 (3.2-56.2 mg/kg) and metamizole (56.2-562.3 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.
Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados, Sede Sur, México, D.F., Mexico. Electronic address: flopez@cinvestav.mx.
Francisco Javier
FJ
López-Muñoz
Luis Alfonso
LA
Moreno-Rocha
Guadalupe
G
Bravo
Uriah
U
Guevara-López
Adriana Miriam
AM
Domínguez-Ramírez
Myrna
M
Déciga-Campos
D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects; D001169:Arthritis, Experimental / Q000188:drug therapy*; D003248:Constipation / Q000139:chemically induced; D004177:Dipyrone / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008297:Male; D059225:Nociception / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D014147:Tramadol / Q000008:administration & dosage* / Q000009:adverse effects
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014147:Tramadol; D004177:Dipyrone
Antinociception; Constipation; Metamizole; PIFIR model; Synergism; Tramadol