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. ED 30 values were estimated for the individual drugs and isobolograms were constructed. Theoretical ED 30 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 ED 30 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.