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.
Pinardi
Gianni
G
Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, PO Box 70.000, Santiago 7, Chile. gpinardi@med.uchile.cl
Prieto
Juan Carlos
JC
Miranda
Hugo F
HF
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D009020:Morphine; D051546:Cyclooxygenase 2