Effects of remifentanil/ketamine mixtures in rats responding under a choice procedure

Despite a number of adverse effects, opioids continue to be the gold standard treatment for moderate to severe pain. One potential way to treat pain while avoiding or reducing adverse effects is to combine opioids with other non-opioid analgesic drugs, thereby decreasing the dose of opioid needed. Our laboratory previously reported that mixing morphine with the N-methyl-D-aspartate antagonist ketamine produced additive or greater than additive effects antinociceptive effects in rats.

The purpose of the present experiment was to determine how ketamine interacts with the opioid agonist remifentanil for reinforcing effects.

This experiment employed an operant choice paradigm, giving rats a concurrent choice between a food pellet alone or a food pellet plus an intravenous infusion. In one group of rats, the effects of remifentanil alone and ketamine alone were determined and compared to saline. In a second group of rats, the effects of remifentanil/ketamine mixtures were determined and compared to saline.

All rats were indifferent to a pellet versus saline + a pellet. When available alone, remifentanil had reinforcing effects, while ketamine had punishing effects. Remifentanil/ketamine mixtures, across a range of doses, had no significant difference from saline. These results demonstrate that ketamine fails to enhance, and might even attenuate, reinforcing effects of remifentanil.

Overall, this adds to the evidence in the literature that combining opioids with non-opioids is a useful strategy for relieving pain while minimizing adverse effects.