Analysis of the analgesic interactions between ketorolac and tramadol during arthritic nociception in rat.
The potential advantage of using combination therapy is that analgesia can be maximized while minimizing the incidence of adverse effects. In order to assess a possible synergistic antinociceptive interactions, the antinociceptive effects of ketorolac tromethamine, p.o., a nonsteroidal anti-inflammatory drug (NSAID), and tramadol hydrochloride, p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally ketorolac alone (0.18, 0.32, 0.56, 1.0, 1.78, 3.16, and 5.62 mg/kg), tramadol alone (3.16, 5.62, 10.0, 17.78, 31.62, 56.23, and 100.0 mg/kg), or 24 different combinations of ketorolac plus tramadol. Ten combinations exhibited various degrees of potentiation of antinociceptive effects (17.78 mg/kg tramadol with either 0.18, 0.32, or 0.56 mg/kg ketorolac; 10.0 mg/kg tramadol with either 0.18, 0.32, 0.56, or 1.8 mg/kg ketorolac; 5.6 mg/kg tramadol with either 0.32 or 0.56 mg/kg ketorolac; and 3.16 mg/kg tramadol with 0.32 mg/kg ketorolac), whereas the other 14 combinations showed additive antinociceptive effects. Three combinations of ketorolac+tramadol (1.0+17.78, 1.78+10, and 1.78+17.78, mg/kg respectively) produced the maximum antinociceptive effects, and two combinations (0.32+10.0 and 0.56+10.0 mg/kg, respectively) presented effects of high potentiation (P<0.001). This combination caused gastric injuries less severe than those observed with indomethacin. The synergistic antinociceptive effects of ketorolac and tramadol were important and suggest that combinations with these drugs may have clinical utility in pain therapy.
López-Muñoz
Francisco Javier
FJ
Laboratorio No. 7, Dolor y Analgesia del Departamento de Farmacobiología, CINVESTAV-IPN, Calzada de los Tenorios No. 235, Col. Granjas Coapa, Deleg. Tlálpan, Mexico, DF, CP 14330 Mexico. flopezm@prodigy.net.mx
Díaz-Reval
Ma Irene
MI
Terrón
José Antonio
JA
Déciga-Campos
Myrna
M
D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D020910:Ketorolac / Q000494:pharmacology* / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D014147:Tramadol / Q000494:pharmacology* / Q000627:therapeutic use
D000700:Analgesics; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014147:Tramadol; D020910:Ketorolac