Antinociceptive effects of ketamine-opioid combinations in the mouse tail flick test

The antinociceptive activities of intraperitoneal (i.p.) ketamine in combination with subcutaneous (s.c.) morphine or fentanyl were studied using the mouse tail flick test, an acute pain model. Morphine and fentanyl exhibited dose-dependent effects, with respective ED50s (95% confidence limits) of 1.3 (1.2-1.4) mg/kg and 6.8 (6.2-7.4) mcg/kg. Ketamine (1, 5, 10 and 20 mg/kg) showed relatively weak antinociceptive effects with no apparent dose-response relationship. In mice pretreated with i.p. ketamine 0.1 mg/kg (no effect on the tail flick reaction time) and 1 mg/kg (antinociceptive), the effects of s.c. morphine (1.5 mg/kg) were enhanced but this was significant only at the higher ketamine dose, whereas fentanyl (6 mcg/kg, s.c.) antinociception was significantly enhanced in both pretreatment groups. The antinociceptive effects of i.p. ketamine (10 and 20 mg/kg) were also studied in mice pretreated with s.c. morphine 0.1 and 0.5 mg/kg or fentanyl 0.5 and 2.5 mcg/kg. Morphine dose-dependently enhanced ketamine antinociception, being significant only at the higher pretreatment dose level. Fentanyl (0.5 mcg/kg) pretreatment significantly enhanced ketamine (20 mg/kg) activity, with no apparent effect on ketamine 10 mg/kg. At 2.5 mcg/kg, fentanyl pretreatment significantly enhanced ketamine antinociception. These results suggest that ketamine may not be as effective in acute pain as opioids are, and that after systemic administration, the net effect of ketamine-opioid combination is a simple additive one.