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Antinociceptive Potentiation and Attenuation of Tolerance by Intrathecal Co-Infusion of Magnesium Sulfate and Morphine in Rats

McCarthy, Robert J. PharmD; Kroin, Jeffrey S. PhD; Tuman, Kenneth J. MD; Penn, Richard D. MD; Ivankovich, Anthony D. MD

doi: 10.1213/00000539-199804000-00028
Regional Anesthesia and Pain Management

N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 [micro sign]g/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 [micro sign]g/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 [micro sign]g/h (10.9 nmol), and magnesium sulfate 60 [micro sign]g/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 [micro sign]g/h) for 2 days increased from 17.0 +/- 1.0 [micro sign]g/mL to 41.4 +/- 23.6 [micro sign]g/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal co-infusion of magnesium sulfate and morphine in the rat. Implications: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.

(Anesth Analg 1998;86:830-6)

Departments of Anesthesiology and Neurosurgery, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois.

Accepted for publication January 13, 1998.

Address correspondence and reprint requests to Robert J. McCarthy, PharmD, Department of Anesthesiology, Rush-Presbyterian-St. Luke's Medical Center, 1653 W. Congress Pkwy., 739 Jelke, Chicago, IL 60612. Address e-mail to

© 1998 International Anesthesia Research Society