Antinociceptive synergy between Δ9-tetrahydrocannabinol and opioids after oral administration

The analgesic effects of opioids, such as morphine and codeine, in mice are enhanced by oral administration of the cannabinoid Delta(9)-tetrahydrocannabinol (Delta(9)-THC). However, isobolographic analysis has never been done to confirm a synergy between Delta(9)-THC and morphine or codeine via oral routes of administration. To determine the nature of the interaction between these drugs for pain relief and extend previous experimental results, we performed an isobolographic analysis to evaluate for additivity or synergy in the tail-flick test. Fixed-ratio combinations of Delta(9)-THC with either morphine or codeine were tested for antinociceptive effects. The experimentally derived ED50 for each combination was compared with the theoretical additive ED50, using an isobolographic analysis. All of the fixed-ratio combinations tested produced greater antinociception (synergy) than predicted from simple additivity. These findings suggest that the use of a low-dose combination of analgesics is a valid and effective approach for the treatment of pain and necessitates further study.