Anti-nociceptive synergism of morphine and gabapentin in neuropathic pain induced by chronic constriction injury.

In order to detect an anti-nociceptive interaction between morphine and gabapentin, the anti-allodynic and anti-hyperalgesic effects of these drugs, administered either separately or in combination, were determined using the von Frey and acetone tests in a rat model of neuropathic pain (Bennett model). Morphine and gabapentin individually induced moderate attenuation of mechanical hyperalgesia, whereas the morphine and gabapentin combination completely decreased hyperalgesia. Morphine showed its maximal effect at 30 min post-injection in the acetone test; however, this effect gradually returned to the baseline value. Gabapentin did not produce an anti-allodynic effect, whereas the morphine and gabapentin combination completely decreased allodynia behavior at 30 min post-injection, an effect that persisted until 120 min. The area under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the combinations were significantly greater than the theoretical sum of effects produced by each drug alone or similar to the theoretical sum. The analysis of the effect, expressed as the AUC of the time course, supports the hypothesis that the combination of these drugs is useful in neuropathic pain therapy.

Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats.

It has been observed that caffeine improves antinociceptive efficacy of some non-steroidal antiinflammatory drugs (NSAIDs) in several experimental models, however, these effects have been questioned in humans. Controversy in clinical studies may be due to the use of different protocols as well as to high interindividual variability in patient response. In addition, the antinociceptive interaction of ibuprofen+caffeine has not been studied. To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ibuprofen, and caffeine administered either separately or in combinations were determined in a model of arthritic pain: "Pain-induced functional impairment in the rat (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine or acetylsalicylic acid alone. The animals were administered with 0.05 ml intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received either acetylsalicylic acid, morphine, ibuprofen or caffeine, or a combination ibuprofen+caffeine (18 combinations). We report here that caffeine (17.8 and 31.6 mg/kg) is able to potentiate the antinociceptive effect of ibuprofen. This investigation showed that six combinations presented effects of potentiation and twelve combinations only showed antinociceptive effects not different from that of ibuprofen alone. The maximum antinociceptive effect was 270.7+/-12.7 area units (au), produced by ibuprofen 100 mg/kg+caffeine 17.8 mg/kg; this effect was greater than the maximum produced by morphine 17.8 mg/kg (244.7+/-22.9 au) in these experimental conditions. The maximum potentiation was 197 % produced with the combination of ibuprofen 17.8 mg/kg+caffeine 17.8 mg/kg. These results suggest that the antinociceptive effect of ibuprofen was significantly potentiated by doses of caffeine that by themselves are ineffective in this model.

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.

Metamizol potentiates morphine antinociception but not constipation after chronic treatment.

This work evaluates the antinociceptive and constipating effects of the combination of 3.2 mg/kg s.c. morphine with 177.8 mg/kg s.c. metamizol in acutely and chronically treated (once a day for 12 days) rats. On the 13th day, antinociceptive effects were assessed using a model of inflammatory nociception, pain-induced functional impairment model, and the charcoal meal test was used to evaluate the intestinal transit. Simultaneous administration of morphine with metamizol resulted in a markedly antinociceptive potentiation and an increasing of the duration of action after a single (298+/-7 vs. 139+/-36 units area (ua); P<0.001) and repeated administration (280+/-17 vs. 131+/-22 ua; P<0.001). Antinociceptive effect of morphine was reduced in chronically treated rats (39+/-10 vs. 18+/-5 au) while the combination-induced antinociception was remained similar as an acute treatment (298+/-7 vs. 280+/-17 au). Acute antinociceptive effects of the combination were partially prevented by 3.2 mg/kg naloxone s.c. (P<0.05), suggesting the partial involvement of the opioidergic system in the synergism observed. In independent groups, morphine inhibited the intestinal transit in 48+/-4% and 38+/-4% after acute and chronic treatment, respectively, suggesting that tolerance did not develop to the constipating effects. The combination inhibited intestinal transit similar to that produced by morphine regardless of the time of treatment, suggesting that metamizol did not potentiate morphine-induced constipation. These findings show a significant interaction between morphine and metamizol in chronically treated rats, suggesting that this combination could be useful for the treatment of chronic pain.