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Anesthesiology 2006; 105:111–9 © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Low-dose Intravenous Ketamine Potentiates Epidural Analgesia after Thoracotomy
Manzo Suzuki, M.D.,* Syuji Haraguti, M.D.,† Kikuzo Sugimoto, M.D., Ph.D.,‡ Takehiko Kikutani, M.D.,* Yoichi Shimada, M.D., Ph.D.,§ Atsuhiro Sakamoto, M.D., Ph.D.Background: Ketamine potentiates intravenous or epidural morphine analgesia. The authors hypothesized that very-lowdose ketamine infusion reduces acute and long-term postthoracotomy pain. Methods: Forty-nine patients scheduled to undergo open thoracotomy were randomly assigned to receive one of two anesthesia regimens: continuous epidural infusion of ropivacaine and morphine, along with intravenousinfusion of ketamine (0.05 mg · kg 1 · h 1 [approximately 3 mg/h], ketamine group, n 24) or placebo (saline, control group, n 25). Epidural analgesia was continued for 2 days after surgery, and infusion of ketamine or placebo was continued for 3 days. Pain was assessed at 6, 12, 24, and 48 h after surgery. Patients were asked about their pain, abnormal sensation on the wound, and inconveniencein daily life at 7 days and 1, 3, and 6 months after surgery. Results: The visual analog scale scores for pain at rest and on coughing 24 and 48 h after thoracotomy were lower in the ketamine group than in the control group (pain at rest, 9 11 vs. 25 20 and 9 11 vs. 18 13; pain on coughing, 26 16 vs. 50 17 and 30 18 vs. 43 18, mean SD; P 0.002 and P 0.01, P < 0.0001 and P 0.02, respectively). Thenumerical rating scale scores for baseline pain 1 and 3 months after thoracotomy were significantly lower in the ketamine group (0.5 [0 – 4] vs. 2 [0 –5] and 0 [0 –5] vs. 1.5 [0 – 6], median [range], respectively; P 0.02). Three months after surgery, a higher number of control patients were taking pain medication (2 vs. 9; P 0.03). Conclusions: Very-low-dose ketamine (0.05 mg · kg 1 · h 1)potentiated morphine–ropivacaine analgesia and reduced postthoracotomy pain.

THORACIC surgery is one of the most painful surgeries. Intercostal nerve damage during surgery induces severe postoperative pain, which may be related to the development of long-term pain after the thoracotomy.1 Katz et al.2 demonstrated that aggressive postoperative pain relief contributes to a reduction in long-termpostoperative
This article is featured in “This Month in Anesthesiology.” Please see this issue of ANESTHESIOLOGY, page 5A.

pain. Compared with patients who received opioid intravenously for postoperative analgesia, patients who received epidural coadministration of opioid and a local anesthetic had a lower incidence of long-term postthoracotomy pain.3 Administration of an opioid during or aftersurgery leads to opioid tolerance and hyperalgesia, which are both mediated by N-methyl-D-aspartate receptor activation.4 A bolus or continuous administration of ketamine during surgery, especially when coadministered with an opioid, provides excellent postoperative analgesia, suggesting that ketamine either prevents acute opioid tolerance or potentiates opioid analgesia.5,6 A study in ratssuggested that administration of ketamine prevents the development of fentanyl-induced hyperalgesia.7 Therefore, we hypothesized that continuous intravenous ketamine infusion at a very low dose of 0.05 mg · kg 1 · h 1, which was expected to produce a plasma ketamine concentration of 20 ng/ml, would potentiate epidural morphine and ropivacaine-induced analgesia after standard open thoracotomy and improvelong-term postoperative pain. To test this hypothesis, we administered a low dose of ketamine or placebo to patients who received an epidural infusion of morphine and ropivacaine for postthoracotomy pain. We then examined the pain status of the patients between 6 and 48 h; at 1 week; and at 1, 3, and 6 months after the completion of thoracotomy. We studied patients who underwent standard open...
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