Opioid Mechanism Involvement in the Synergism Produced by the Combination of Diclofenac and Caffeine in the Formalin Model

Abstract

Analgesics can be administered in combination with caffeine for improved analgesic effectiveness in a process known as synergism. The mechanisms by which these combinations produce synergism are not yet fully understood. The aim of this study was to analyze whether the administration of diclofenac combined with caffeine produced antinociceptive synergism and whether opioid mechanisms played a role in this event. The formalin model was used to evaluate the antinociception produced by the oral administration of diclofenac, caffeine, or their combination. Opioid involvement was analyzed through intracerebroventricular (i.c.v.) administration of naloxone followed by the oral administration of the study drugs. Diclofenac presented a dose-dependent effect, with a mean effective dose (ED50) of 6.7 mg/kg. Caffeine presented an analgesic effect with a 17-36% range. The combination of subeffective doses of each of the two drugs presented the greatest synergism with an effect of 57.7 ± 5.6%. The maximal antinociceptive effect was obtained with the combination of 10.0 mg/kg diclofenac and 1.0 mg/kg of caffeine, with an effect of 76.7 ± 5.6%. The i.c.v. administration of naloxone inhibited the effect of diclofenac, both separately and combined. In conclusion, caffeine produces antinociceptive synergism when administered in combination with diclofenac, and this synergism is partially mediated by opioid mechanisms at the central level.

Figure 1

The DRC of oral diclofenac (DIC) in doses of 0.316, 1.0, 3.16, 10.0, 31.6, and 56.2 mg/kg and oral caffeine (CAF) in doses of 1, 1.78, and 3.16 mg/kg. For each dose, the mean of 6 determinations ± S.E.M. was plotted on the graph.

Figure 2

The DRC of the combinations of diclofenac (DIC) and caffeine (CAF) compared with the DRC of DIC administered separately. Both drugs were administered orally. Each dose represents the mean of an n = 6 ± S.E.M. ^* P < 0.05 group that was administered with combination (DIC + CAF 1 mg/kg) versus the animals that only received DIC.

Figure 3

The effect of caffeine (CAF) administered in combination with diclofenac (DIC) in the formalin model. (a) The white bars show the effect of DIC (0.316 mg/kg) and CAF (1 mg/kg) when administered separately by oral route; the black bar shows the effect of the drug combinations at the indicated doses. (b) The white bars show the effect of DIC (10 mg/kg) and CAF (1 mg/kg) when administered separately by oral route; the black bar shows the effect of the drug combinations at the indicated doses. For each treatment the mean of an n = 6 ± S.E.M. was plotted on the graph.

Figure 4

The effect of i.c.v. naloxone (NX, 12.13 µg/rat) on the antinociception produced by diclofenac (DIC, 31.6mg/kg), caffeine (CAF, 1.78 mg/kg), or their combination (DIC 0.316 mg/kg and CAF 1 mg/kg) is shown by the black bars compared with the same drugs with i.c.v. saline solution (white bars). The mean of six determinations ± S.E.M. was plotted on the graph. ^* P < 0.05 for the group with DIC but without NX. ^# P < 0.05 for the group with DIC + CAF but without NX.