TY - JOUR
T1 - Analysis of the analgesic interactions between ketorolac and tramadol during arthritic nociception in rat
AU - López-Muñoz, Francisco Javier
AU - Díaz-Reval, Ma Irene
AU - Terrón, José Antonio
AU - Déciga Campos, Myrna
PY - 2004/1/26
Y1 - 2004/1/26
N2 - 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.
AB - 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.
KW - Cyclooxygenase
KW - Inflammatory pain
KW - Ketorolac
KW - Synergism
KW - Tramadol
UR - http://www.scopus.com/inward/record.url?scp=1642423756&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2003.11.005
DO - 10.1016/j.ejphar.2003.11.005
M3 - Artículo
SN - 0014-2999
VL - 484
SP - 157
EP - 165
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2-3
ER -