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REGIONAL ANESTHESIA

The Antinociceptive Effect of the Combination of Spinal Morphine with Systemic Morphine or Buprenorphine

Alexander Nemirovsky, MD, PhD^*, Lianhua Chen, MD^*, Vladimir Zelman, MD, PhD^*, and Ilmar Jurna, DrMed

Departments of *Anesthesiology and Cell & Neurobiology, University of Southern California, Los Angeles, California; and Medizinische Fakultät der Universität des Saarlandes, Homburg, Germany

Address correspondence and reprint requests to Alexander Nemirovsky, MD, PhD, Department of Anesthesiology, University of Southern California, 1200 N. State St., Ste. 14-901, Los Angeles, CA 90033. Address e-mail to anemirovsky{at}hotmail.com

We sought to analyze the mode of interaction of spinal morphine with systemic morphine or buprenorphine, administered in a wide range of antinociceptive doses. The study was performed on Sprague-Dawley rats by using a plantar stimulation test and isobolographic and fractional analyses of drug interaction. The isobolographic and fractional analyses demonstrated that intrathecal morphine interacted with subcutaneous morphine in a synergistic manner while producing a 50% or 75% antinociceptive effect. The sum of D₇₅ fractions was more than that for 50% antinociception, suggesting a less dramatic interaction. The combination with a maximal relative dose of systemic morphine (0.66:1) showed a maximal degree of supraadditivity. The interaction between spinal morphine and systemic buprenorphine was similar to that of morphine/morphine, although the supra-additivity was not as pronounced. For the doses that produced a 50% antinociceptive effect, a synergistic interaction was observed only for the combination with a morphine/buprenorphine ratio of 1.33:1. When the relative amount of intrathecal morphine was decreased or increased, the effect became additive. At the doses that produced 75% antinociception, both combinations of morphine and buprenorphine demonstrated supraadditive interaction.

Implications: Spinal morphine interacts with systemic morphine or buprenorphine in asupraadditive manner. This mode of interaction most probably results from thesimultaneous activation of spinal and supraspinal antinociceptive systems.Supraspinal structures played a more important role in the antinociceptiveeffect of experimental combinations than structures of the spinal cord.

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