Anesth Analg 2008; 107:1041-1044
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31817f1e4a
ANALGESIA
Continuous Low-Dose Ketamine Improves the Analgesic Effects of Fentanyl Patient-Controlled Analgesia After Cervical Spine Surgery
Masanori Yamauchi, MD, PhD*,
Makoto Asano, MD, PhD ,
Masanori Watanabe, MD*,
Soushi Iwasaki, MD, PhD*,
Shingo Furuse, MD*, and
Akiyoshi Namiki, MD, PhD*
From the *Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Anesthesia, Oji General Hospital, Tomakomai, Japan.
Address correspondence and reprint requests to Masanori Yamauchi, Department of Anesthesiology, Sapporo Medical University School of Medicine, S1 W16 Chuo-ku, Sapporo, Hokkaido 060-8543, Japan. Address e-mail to yamauchi{at}sapmed.ac.jp.
Abstract
BACKGROUND: The effects of fentanyl with ketamine for postoperative pain are unknown. We investigated the adjuvant effects of ketamine for fentanyl patient-controlled analgesia.
METHODS: Cervical and lumbar spine surgery patients were divided into three groups: ketamine 1 mg/kg followed by 42 and 83 µg · kg–1 · h–1 in ketamine-1 and ketamine-2 group, respectively, and a control group. Postoperative patient-controlled analgesia fentanyl was administered with a background infusion.
RESULTS: Pain scores and analgesia requirement in the ketamine-2 group were significantly lower than those of the control group after cervical surgery. Ketamine partially improved the analgesic effects of fentanyl after lumbar surgery.
CONCLUSION: Small-dose ketamine improved the analgesic effects of fentanyl after cervical surgery.
Although fentanyl is used for postoperative analgesia via a patient-controlled analgesia (PCA) system, the incidence of side effects increases in proportion to the serum concentration.1–3 Furthermore, hyperalgesia or acute tolerance may be induced by high doses of opioids.4,5 It has been reported that ketamine enhances the analgesic effects of morphine and reduces the incidence of side effects and development of tolerance,6–10 thus co-administration of fentanyl and ketamine may achieve a better quality of postoperative state than that of fentanyl alone.11–13 In this study, we investigated the effects of small-dose ketamine for postoperative IV PCA fentanyl after cervical and lumbar spine surgery.
METHODS
After IRB approval and written informed consent, 202 patients ASA physical status I or II, aged 20–70 yr, and undergoing posterior cervical or lumbar spinal surgery were prospectively randomized by an envelope method in a double-blind manner. Exclusion criteria included chronic pain syndrome, history of opioid or steroid use, and severe surgical area pain. Anesthesia was induced with propofol 2–3 mg/kg and fentanyl 2 µg/kg and maintained by sevoflurane 1–3% and nitrous oxide 60% in oxygen with tracheal intubation. The patients were divided into three groups according to the IV infusion regimens at the skin incision (ket-1 group; bolus ketamine 1 mg/kg followed by continuous ketamine 42 µg · kg–1 · h–1 for 24 h (1 mg/kg), ket-2 group; bolus ketamine 1 mg/kg followed by continuous ketamine 83 µg · kg–1 · h–1 for 24 h (2 mg/kg), control group; isotonic saline was administered). The PCA was programmed to deliver 0.5 µg · kg–1 · h–1 of fentanyl on basal infusion and 0.5 µg/kg on demand with 6 minutes lockout for 48 h. The pain score assessed by visual analog scale was observed for 10 days. Nonsteroidal antiinflammatory drugs (NSAIDs) (diclofenac suppository 50 mg) were administered at the end of surgery to all patients, and if necessary, patients could freely request NSAIDs every 8 h. PCA fentanyl consumption, NSAIDs requirements and side effects (postoperative nausea and vomiting (PONV), respiratory or circulatory depression, pruritus, disturbing dreams, urinary retention, and hallucination) were observed for 3 days. The side effects were assessed by four grade scores (0 = none, 1 = mild, 2 = discomfort, and 3 = worst or requiring of rescue medication). Satisfaction with pain control for 5 days after the surgery was scored by visual analog scale (Table 1).
The sample size was defined by fentanyl consumption dose and 22 patients per group gave the study a power of 0.8 and a Type I error of 0.05. Data were analyzed by unpaired two-tailed Student’s t-test, by two-way repeated-measures analysis of variance followed by Fisher’s PLSD test or the  2 test, and expressed as mean ± sd P < 0.05 was considered significant.
RESULTS
Of the 202 patients, 2 were excluded because of postoperative fever and hematoma, respectively. Data of all patients were included in this investigation until the sample number of each group reached 22. After cervical surgery, pain scores in the ket-2 group were significantly lower than those in the control group for 48 h and lower than in ket-1 group for 24 h (Fig. 1). Fentanyl consumption dose (Fig. 2) and NSAIDs requirement (Table 2) in the ket-2 group were significantly less than groups in cervical surgery. In lumbar surgery, there were some early time points with significantly lower pain scores at rest with the ket-2 group, but there were no significant differences on movement (Fig. 3). In lumbar surgery, fentanyl consumption in the ket-2 group was significantly less than in the control group at only the 6-h time point (Fig. 4). Postoperative nausea and vomiting score in the ket-2 group after cervical surgery was significantly lower than in any other group (Table 2). No patient was administered naloxone to treat side effects. Satisfaction score in the ket-2 group was significantly higher than in control group after cervical surgery (Table 3).
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Figure 1. Postoperative pain score of the cervical surgery for 10 postoperative days. Mean ± sd *P < in ket-2 Group 0.05 versus control group, P < 0.05 versus ket-1 group. VAS = visual analog score of postoperative pain; ket-1 = continuous ketamine 1 mg · kg–1 · 24 h–1 group; ket-2 = continuous ketamine 2 mg · kg–1 · 24 h–1 group.
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Figure 2. Total fentanyl consumption dose after the cervical surgery. Mean ± sd *P < 0.05 versus control group, P < 0.05 versus ket-1 group. ket-1 = continuous ketamine 1 mg · kg–1 · 24 h–1 group; ket-2 = continuous ketamine 2 mg · kg–1 · 24 h–1 group.
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Figure 3. Postoperative pain score of the lumbar surgery for 10 postoperative days. Mean ± sd *P < in ket-2 Group 0.05 versus control group, P < 0.05 versus ket-1 group. VAS = visual analog score of postoperative pain; ket-1 = continuous ketamine 1 mg · kg–1 · 24 h–1; ket-2 = continuous ketamine 2 mg · kg–1 · 24 h–1.
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Figure 4. Total fentanyl consumption dose after the lumbar surgery. Mean ± sd *P < 0.05 versus control group. ket-1 = continuous ketamine 1 mg · kg–1 · 24 h–1 group; ket-2 = continuous ketamine 2 mg · kg–1 · 24 h–1 group.
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DISCUSSION
In cervical spine surgery, ketamine 2 mg · kg–1 · 24 h–1 enhanced analgesic effects of PCA fentanyl, reduced side effects, and increased patient satisfaction. Fentanyl may be used for postoperative PCA analgesia as an alternative to morphine. As duration of analgesia of fentanyl boluses is brief, a background infusion was used in this study. Reports of the effects of ketamine with morphine have been conflicting. Some studies have reported that small-dose ketamine (30–150 µg · kg–1 · h–1) reduced pain scores, the incidence of adverse effects of morphine, and PCA morphine requirement.8,9 Himmelseher and Durieux reported that a morphine:ketamine ratio of 1:1 was optimal.10 However, some have reported that co-administration of morphine and ketamine could not be recommended to reduce opioid consumption or side effects,14,15 and that larger doses of ketamine would be required to treat severe pain or visceral pain.16 Differing findings may depend on the dose of ketamine and the severity of postoperative pain. In our investigation, ketamine improved postoperative pain, reduced side effects and fentanyl use after cervical spine surgery, but could not do so after lumbar surgery. The mechanism of the adjuvant ketamine may be because of noncompetitive N-methyl-d-aspartate glutamate receptor antagonist, as well as sodium channel blocker.10,17 A preemptive analgesic effect18 and a synergistic effect between fentanyl and ketamine19 may also contribute. We speculate that these effects could modulate affective pain processing and opioid induced tolerance and hyperalgesia.11–13 In conclusion, small-dose ketamine enhanced the analgesic effects of fentanyl, and reduced side effects in cervical spine surgery. Further study is required to determine optimal dosages of ketamine and fentanyl and what types of pain could be suppressed by small-dose ketamine.
Footnotes
Accepted for publication April 29, 2008.
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