Therapeutic Advantage For Clinical Treatment Research Articles

Synergistic interaction of diclofenac, benfotiamine, and resveratrol in experimental acute pain

AbstractThis study was designed to evaluate the possible synergistic antinociceptive interactions between diclofenac, benfotiamine, and resveratrol on acetic acid‐induced nociception in mice. Isobolographic analyses were used to define the nature of the interactions between drugs. Diclofenac, benfotiamine, or resveratrol, as well as their combinations, produced a dose‐dependent antinociceptive effect. ED30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED30 values for the combinations estimated from the isobolograms were 170.9±23.4, 4.9±1.0, and 173.3±11.8 mg/kg for the diclofenac+benfotiamine, diclofenac+resveratrol, or benfotiamine+resveratrol combination, respectively. These values were significantly higher than the actually observed ED30 values, which were 10.2±1.9, 0.3±0.1, and 5.3±0.8 mg/kg, respectively, indicating a synergistic interaction in the three combinations. Data indicate that low doses of the diclofenac+benfotiamine, diclofenac+resveratrol, or benfotiamine+resveratrol combination can interact synergistically to reverse acetic acid‐induced nociception and they may represent a therapeutic advantage for clinical treatment of inflammatory pain. Drug Dev Res 72: 397–404, 2011. © 2011 Wiley‐Liss, Inc.

Synergic Antinociceptive Interaction between Tramadol and Gabapentin after Local, Spinal and Systemic Administration

The possible interaction between tramadol and gabapentin on formalin-induced nociception in the rat was assessed. Tramadol, gabapentin or a fixed-dose ratio combination of gabapentin and tramadol were administered peripherally, spinally and orally to rats, and the antinociceptive effect was determined in the 1% formalin test. Isobolographic analyses were used to define the nature of the interactions between drugs. Tramadol, gabapentin and tramadol-gabapentin combinations produced a dose-dependent antinociceptive effect when administered locally, spinally or orally. ED₃₀ values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED₃₀ values for the combination estimated from the isobolograms were 126.8 ± 11.1 µg/paw, 23.1 ± 2.6 µg/rat, and 2.23 ± 0.32 mg/kg for the local, intrathecal and oral routes, respectively. These values were significantly higher than the actually observed ED₃₀ values which were 13.3 ± 2.1 µg/paw, 8.1 ± 0.6 µg/rat and 0.71 ± 0.10 mg/kg, indicating a synergistic interaction. Although efficacy was not improved, local peripheral administration resulted in the highest increase in potency, being about tenfold. Spinal and systemic administration increased potency threefold. Data indicate that low doses of the tramadol-gabapentin combination can interact synergistically to reverse formalin-induced nociception and may represent a therapeutic advantage for clinical treatment of inflammatory pain.

Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia.

Gabapentin and pregabalin are anticonvulsants with antihyperalgesic effects in animal models of neuropathic and inflammatory nociception. This study characterized the manner in which gabapentin or pregabalin interacts with naproxen to suppress thermal hyperalgesia and inflammation in the carrageenan model of peripheral inflammation. Gabapentin, pregabalin, naproxen, or a fixed-dose ratio of gabapentin + naproxen or pregabalin + naproxen was administered orally to rats after the induction of inflammation by intraplantar injection of lambda-carrageenan in one hind paw. Nociceptive thresholds were determined by the radiant heat paw-withdrawal test. Paw edema was measured by plethysmometry. Drug plasma concentrations were determined by a liquid chromatography-mass spectroscopy-mass spectroscopy method. Gabapentin, pregabalin, and naproxen alone reversed thermal hyperalgesia with ED50 values of 19.2, 6.0, and 0.5 mg/kg, respectively. Mixtures of gabapentin + naproxen in fixed-dose ratios of 50:1, 10:1, or 1:1 interacted synergistically to reverse carrageenan-induced thermal hyperalgesia. However, 1:50 gabapentin + naproxen produced only additive effects. No combination of gabapentin + naproxen decreased paw edema in a manner greater than additive. Plasma concentrations of gabapentin and naproxen were unaltered by the addition of the other drug. The mixture of 10:1 of pregabalin + naproxen interacted synergistically to reverse thermal hyperalgesia on the inflamed hind paw, whereas mixtures of 1:1 or 1:10 produced additive effects. These data suggest that gabapentin + naproxen and pregabalin + naproxen can interact synergistically or additively to reverse thermal hyperalgesia associated with peripheral inflammation. Therefore, the use of gabapentin or pregabalin in low-dose combinations with naproxen may afford therapeutic advantages for clinical treatment of persistent inflammatory pain.