Analgesic synergism between intrathecal morphine and cyclooxygenase-2 inhibitors in mice

The analgesic effects of the intrathecal coadministration of morphine with nimesulide, meloxicam and parecoxib, preferential cyclooxygenase-2 (COX-2) inhibitors, were studied in mice using a chemical model of visceral pain, the acetic acid writhing test. Isobolographic analysis was used to characterize the interactions between mixtures of morphine with each non-steroidal anti-inflammatory drug. Antinociception dose-response curves were analyzed to obtain the ED50's of each drug. A dose response curve for fixed ratio mixtures of morphine with COX-2 inhibitors was then performed and the observed ED50's were plotted on a two-dimensional isobologram. All the combinations tested showed synergistic interactions and the strength of the interaction was ranked as: morphine/parecoxib>morphine/meloxicam>morphine nimesulide. The results demonstrate that the intrathecal coadministration of COX-2 inhibitors significantly enhance morphine-induced antinociception and could result in an opioid sparing action which may be useful in the clinical treatment of severe pain. A sparing action means that less opioids have to be administered to obtain a given analgesic effect. Since intrathecal morphine is often used in clinical pain situations, the opioid sparing effect resulting from the synergy observed with the coadministration of COX-2 inhibitors may be clinically relevant. One of the most significant advantages should be the reduction of opioid toxicity which often acts as a major obstacle in pain treatment.