Anesth Analg 2000;90:136
© 2000 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MANAGEMENT
Spinal Coadministration of Ketamine Reduces the Development of Tolerance to Visceral As Well As Somatic Antinociception During Spinal Morphine Infusion
H. Miyamoto, MD,
Y. Saito, MD,
Y. Kirihara, DVM,
K. Hara, MD,
S. Sakura, MD, and
Y. Kosaka, MD
Department of Anesthesiology, Shimane Medical University, Izumo, Japan
Address correspondence to Y. Saito, MD, Department of Anesthesiology, Shimane Medical University, 89-1 Enya-cho, Izumo City, Shimane 693-8501, Japan. Address e-mail to ysaito{at}shimane-med.ac.jp
This study was designed to investigate the effects of ketamine, an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to morphine and morphine antinociception during intrathecal infusion. Two intrathecal catheters were implanted in the subarachnoid space in male rats under pentobarbital anesthesia. One catheter was used for the intrathecal infusion with the following solutions: morphine 1 µg · kg-1 · hr-1 (M1) and 5 µg · kg-1 · hr-1 (M5); ketamine 250 µg · kg-1 · hr-1 (K250); morphine plus ketamine, 1 µg · kg-1 · hr-1 plus 250 µg · kg-1 · hr-1 (M1 + K250) and 5 µg · kg-1 · hr-1 + 250 µg · kg-1 · hr-1 (M5 + K250); or saline. The other catheter was used for morphine challenge tests. The responses to noxious somatic and visceral stimuli were measured by tail flick (TF) and colorectal distension (CD) tests, respectively. Measurements were performed once a day for 7 days. Challenge tests with intrathecal morphine were performed to assess the magnitude of tolerance on Day 5 and Day 7. The antinociceptive effect was evaluated by using the percent of maximal possible effect (%MPE). Morphine infusion produced significant increases in %MPEs in TF and CD tests, while the saline and K250 infusions did not show any changes. The M1 + K250 infusion significantly increased the %MPEs in TF and CD tests, although the M1 and K250 infusions alone showed no changes. M5 + K250 enhanced the increases of %MPEs in TF and CD tests compared with the M5 infusion alone. In the challenge tests, the M1 + K250 infusion showed no significant decrease in %MPEs and TF and CD tests. The M5 + K250 infusion significantly inhibited those decreases in %MPEs, although the M5 infusion showed significant decreases in TF and CD tests. We concluded that ketamine attenuated the development of morphine tolerance to antinociceptive effects and increased the somatic and visceral antinociception of morphine.
Implications: Intrathecally co-infused ketamine attenuated morphine tolerance to somatic and visceral antinociception and increased morphine antinociception at the spinal level. These results suggest that a combination of morphine with ketamine may have an advantage in long-term use of opioids for controlling visceral as well as somatic pain.
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