title: Additive, but not synergistic antinociceptive effect of codeine and indomethacin combinations in the formalin test in the rat.
abstract: Combinations of NSAIDs and opioids are currently employed for the treatment of moderate-to-severe pain in order to obtain an increased analgesic esponse, allowing the use of low doses of each agent, hence limiting side effects. There is active interest in developing combinations for oral adminstration. Therefore, we examined the antinociceptive activity of oral indomethacin and codeine, alone and incombination, in the formalin test in the rat. Both codeine and indomethacin, when given alone, produced a dose-dependent antinociceptive effect. ED30 values were 5.0 +/- 0.31 and 54.8 +/- 5.8 mg/kg for codeine and indomethacin respectively. Codeine-indomethacin combinations also produced a dose-dependent antinociceptive effect. The interaction between these two agents was characterized by isobolographic analysis using a fixed-ratio dosing strategy. Accordingly, the theoretical ED30 of the combination for a pure additive interaction, (i.e., that the combined effect is the result of the sum of the effects of the individual components), was 29.9 +/- 2.9 mg/kg. The observed ED30 for the codeine-indomethacin combination was 21.7 +/- 2.34 mg/kg. Comparison by the Student "t" test showed that there is no statistically significant difference (p > 0.05) between the observed and the theoretical DE30 values and thus a synergistic interaction is ruled out. We conclude that the indomethacin-codeine interaction is additive and does not result in analgesic synergism, unlike other combinations such as codeine-diclofenac. Our results show that, since not all the opioid-NSAID associations result in synergism, the individual components of a combination should be carefully selected, and that mechanisms of synergy may suggest actions of the NSAID partner not previously known.
authors.affiliation: Instituto Mexicano del Seguro Social, México.
authors.forename: Teresa
authors.initials: T
authors.lastname: Arredondo-Garza
authors.forename: Jair
authors.initials: J
authors.lastname: Lozano-Cuenca
authors.forename: Miguel
authors.initials: M
authors.lastname: Jiménez-Andrade
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernández
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003061:Codeine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D005557:Formaldehyde; D007213:Indomethacin / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D005557:Formaldehyde; D003061:Codeine; D007213:Indomethacin