Assessment of the antinociceptive effects of pregabalin alone or in combination with morphine during acetic acid-induced writhing in mice

Visceral pain currently represents one of the most important pain treatment challenges in clinical practice, and investigators across the world are continuously designing and conducting numerous studies in search of new analgesics and new combination therapies. The current study assessed the analgesic effects of saline, pregabalin (2, 5, 17, 50, 100, and 200 mg/kg, i.p.) and morphine (0.25, 0.5, 1, 3 and 5 mg/kg) alone or in combination on acetic-acid induced abdominal contractions in mice. The number of writhes and the inhibitory effects (as percentages, %E) were calculated as antinociception indexes. These indexes indicated that both pregabalin (Prg) and morphine (Mrp) produced dose-dependent antinociception. Pregabalin at 5 mg/kg (%E = 32.5 ± 4.0) or 2 mg/kg (%E = 20.8 ± 4.5) and morphine at 0.25 mg/kg (%E = 20.2 ± 7.8) and 0.5 mg/kg (%E = 43.6 ± 4.5) exhibited antinociceptive effects, and the combination of pregabalin and morphine produced significantly greater antinociceptive effects (%E = 62.4 ± 5.8 for Prg5 + Mrp0.25; %E = 71.7 ± 4.8 for Prg5 + Mrp0.5; and %E = 54.1 ± 4.0 for Prg2 + Mrp0.25), although this enhancement was not observed when morphine was combined with 17 mg/kg pregabalin. Pre-treatment with 2 mg/kg (i.p.) naloxone did not affect increased analgesia when combined with these drugs. A dose-response curve was established for pregabalin at a fixed morphine dose and revealed that, at low doses, pregabalin dose-dependently enhanced the antinociceptive effects, while the opposite was true at high doses (17 and 25 mg/kg). In conclusion, pregabalin can produce levels of antinociception that are similar to those of morphine in acetic acid-induced viscero-somatic pain. The enhancement of antinociception produced by the co-administration of morphine and pregabalin is termed a supra-additive interaction and occurred at low doses but not at high doses. These findings militate for increased attention and caution in clinical settings.