Anesth Analg 2004;98:1413-1418
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000111204.31815.2D
PAIN MEDICINE
Improvement of Pain Treatment After Major Abdominal Surgery by Intravenous S(+)-Ketamine
Helena Argiriadou, MD*,
Sabine Himmelseher, MD
,
Pinelopi Papagiannopoulou, MD
,
Mary Georgiou, MD,
Fotios Kanakoudis, MD,
Maria Giala, MD*, and
Eberhard Kochs, MD PhD
*Department of Anesthesiology, AHEPA University Hospital, Thessaloniki, Greece;
Klinik für Anaesthesiologie, Technische Universität München, Munich, Germany; and
Department of Anesthesiology, G. Gennimatas University Hospital, Thessaloniki, Greece
Address correspondence and reprint requests to Helena Argiriadou, MD, Department of Anesthesiology, AHEPA University Hospital, St. Kyriakidi 1, 54636 Thessaloniki, Greece. Address e-mail to papaziog{at}med.auth.gr
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Abstract
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The use of intraoperative racemic ketamine for pain prevention after abdominal surgery is controversial. We compared one preincisional IV injection of S(+)-ketamine with its preincisional and repeated intraoperative use in 45 patients undergoing surgery with epidural and general anesthesia. S(+)-ketamine is a new drug formulation that contains the more potent S(+)-stereoisomer of ketamine. Patients were randomized to receive placebo, 0.5 mg/kg preincisional S(+)ketamine, or 0.5 mg/kg preincisional and 0.2 mg/kg intraoperative S(+)-ketamine repeated at 20-min intervals. In the postoperative period, epidural ropivacaine (2 mg/mL; 0.12 mL · kg–1 · h–1) was infused for pain therapy. Patients who received repeated S(+)-ketamine reported smaller pain scores than those who received placebo after awakening and 3 and 6 h later (P 
0.05). Fewer patients with repeated S(+)-ketamine required additional analgesics than those with placebo (P 0.05). Cumulative consumption of additional diclofenac and dextropropoxyphene at 24 h was less after single (P < 0.05) and repeated (P < 0.05) S(+)-ketamine versus placebo. After awakening, patients who received repeated S(+)-ketamine reported being in a better mood than those in the other groups (P < 0.05). No psychotomimetic side effects were noted. In conclusion, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone.
IMPLICATIONS: After major visceral surgery, preincisional and repeated intraoperative small-dose S(+)-ketamine added to general and epidural anesthesia causes better postoperative pain relief than general and epidural anesthesia alone.
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Introduction
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The clinical utility of intraoperative pain prevention with the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine in abdominal surgery has been questioned on the basis of studies reporting a lack of improved postoperative pain relief (1–3). However, considering the long-lasting injury process caused by surgical trauma, one injection of IV ketamine before incision may not be sufficient to reduce postoperative pain (4).
S(+)-ketamine, the left-handed optical isomer of racemic ketamine, has a fourfold higher affinity for NMDA receptors than its stereoisomer R(–)-ketamine (5,6). Investigational trials have reported that this results in an analgesic potency of S(+)-ketamine that is approximately twice that of racemic ketamine (7–10). When S(+)-ketamine was used at half the dose of racemic ketamine for surgical anesthesia in early studies, patients who received S(+)-ketamine experienced less postoperative pain and said they were in a better mood (7). In healthy volunteers, half-dose S(+)-ketamine induced less decline in intellectual capacities than racemic ketamine at equianalgesic effects (10). In some European countries, S(+)-ketamine has recently been approved for clinical use. The novelty of this formulation is based on the drug preparation that contains pure S(+)-ketamine.
In this study, we evaluated whether preincisional versus preincisional and repeated intraoperative IV S(+)-ketamine added to a combined general and epidural anesthesia regimen offers improved pain relief after major lower abdominal surgery. We hypothesized that postoperative pain would be less after multiple-dose S(+)-ketamine than after placebo or single-dose S(+)-ketamine.
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Methods
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With institutional ethics committee approval and informed consent, patients scheduled for major abdominal surgery under epidural and general anesthesia were included in this double-masked randomized trial. Exclusion criteria included age <18 yr or more than 75 yr; weight <45 kg or >120 kg; evidence of severe cardiovascular, renal, hematologic, or hepatic disease; ASA physical status higher than III; preexisting neurological or psychiatric illnesses; chronic pain syndromes; alcohol or drug abuse; contraindications for epidural anesthesia or for any of the anesthetics or study drugs used; and difficulties in cooperation between physician and patient. Patients were instructed on the use of a 10-cm visual analog score (VAS) scale (from 0 = no pain to 10 = worst pain imaginable) during the preoperative visit.
Patients were premedicated with oral diazepam (0.15 mg/kg) 1 h before surgery. In the operating room, lactated Ringer’s solution 10–15 mL/kg was given before surgery. Lumbar epidural catheter placement was performed by using standard a loss-of-resistance technique at the L3-4 interspace (variations were allowed from L2 through L4). Ten minutes after a 3-mL test dose of lidocaine (20 mg/mL), ropivacaine (10 mg/mL) was titrated in 5-mL aliquots to a sensory block of dermatome T6.
After epidural anesthesia had been established, general anesthesia was induced with propofol (2–3 mg/kg) and fentanyl (2–4 µg/kg). Cisatracurium (0.15 mg/kg) was used to facilitate tracheal intubation. For muscle relaxation, an infusion of cisatracurium (initial rate of 1.5 µg · kg–1 · min–1) was adjusted to maintain a 10%–20% T1/T0 ratio by using train-of-four stimulation of the right ulnar nerve. Anesthesia was maintained with sevoflurane (1%–3%) and oxygen (33%) in air. If heart rate or arterial blood pressure exceeded 20% of baseline values, another aliquot of ropivacaine was provided as considered necessary by the attending anesthesiologist. Cisatracurium was stopped at the beginning of abdominal closure, and sevoflurane was discontinued on surgical skin closure. If the T1/T0 ratio was <90% at completion of skin closure, muscle relaxation was reversed with atropine (0.01 mg/kg) and neostigmine (0.05 mg/kg). Spontaneously breathing patients were tracheally extubated in the absence of hypercapnia and decreased respiratory rate when they were able to follow commands.
With use of a computer-generated randomization table, patients were assigned to one of three groups. The placebo group received preincisional and repeated intraoperative isotonic saline. The single S(+)-ketamine group received a single IV injection of S(+)-ketamine 0.5 mg/kg before incision and repeated isotonic saline during surgery. The repeated S(+)-ketamine group received S(+)-ketamine 0.5 mg/kg before incision and intraoperative S(+)-ketamine 0.2 mg/kg repeated at 20-min intervals until 30 min before the end of surgery. This dosing schedule was based on open-label pilot studies in the same setting. We preferred repeated injections instead of a continuous ketamine infusion because we saw the same pain-preventive effects after either mode of use. With repeated use, there is no need for expensive infusion devices. Drug injections were slowly performed over 3 min. Patients and personnel who participated in the study were unaware of group assignment.
After awakening, which was defined as the patient’s ability to open the eyes, grip one finger, and correctly answer questions regarding orientation to person, time and place, motor blockade was assessed bilaterally with a modified Bromage scale (0 = no motor block, 1 = ability to move knee and ankle, 2 = ability to move ankle, and 3 = inability to move ankle). When the score was <2, patients received a continuous epidural infusion of 0.2% ropivacaine at 0.12 mL · kg–1 · h–1 for 48 h.
Postoperative evaluations were recorded after awakening as well as 3, 6, and 24 h later. Pain intensity was assessed with the VAS scale. Additional analgesics were administered on the basis of a standardized protocol. If VAS scores were more than 3, diclofenac (a nonsteroidal antiinflammatory drug) was provided as a suppository. In case of pain persistence for 30 min after diclofenac administration, IV dextropropoxyphene (synthetic opioid) was titrated until the VAS score was less than 2. Any adverse events were noted. At each evaluation, patients were questioned about psychological effects, hallucinations, or dreams that could be related to ketamine.
After awakening, patients were asked to qualitatively describe their mood status. Investigators presented the following adjectives to assess six subsets of mood states (10): "tense/relaxed," "happy/sad," "agitated/calm," "afraid/brave," "alert/drowsy," and "depressed/euphoric." Patients were requested to choose an adjective only if they felt that this adjective indicated their current mood. If they felt that no adjective was appropriate, this selection was counted as zero.
On the basis of pilot studies, we hypothesized that we would observe at least a 20% reduction in the number of patients who required additional analgesics after preincisional and repeated S(+)-ketamine versus preincisional S(+)-ketamine. Power calculations suggested that a group size of 15 patients should provide a 95% chance of detecting such a difference at a 0.05 level of significance. Parametric data are expressed as mean ± SD after verification of normal distribution with the Kolmogorov-Smirnov test. Analysis of variance with Tukey’s test was used for comparisons among groups. Nonnormally distributed data are reported as median and range (first and third quartiles). The Friedman test and Wilcoxon’s signed rank post hoc test with Bonferroni’s correction were used for analysis. Proportions were compared with contingency table analysis, followed by Fisher’s exact test with the Yates’ correction if appropriate.
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Results
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Fifty-two patients were enrolled. One patient had to be withdrawn because of failure to place the epidural catheter and one because of a Bromage score more than 2 for more than two postoperative hours. Premature study discontinuation occurred in two patients with placebo: in one patient who developed postoperative fever for which the catheter was removed and in one patient who had early postoperative catheter dislocation. Three patients who received single S(+)-ketamine were excluded: one patient had a pulmonary embolism that required postoperative intubation and therapy, and two patients lacked adherence to the analgesia protocol.
Patient, preoperative, and intraoperative data were similar among groups (Table 1). Additional intraoperative ropivacaine was used in eight patients with placebo, six patients with single S(+)-ketamine, and three patients with repeated S(+)-ketamine. The last ropivacaine dose was used 35 min (25.8–44.2 min) before the end of surgery after placebo, 40 min (32.7–47.3 min) after single S(+)-ketamine, and 50 min (48–62 min) after repeated S(+)-ketamine.
After awakening, patients who received repeated S(+)-ketamine rated their mood to be better than those who received single S(+)-ketamine or placebo. Patients with repeated S(+)-ketamine felt "happy, calm, and euphoric" (P 0.05), and patients with placebo indicated they were "alert" (P 0.05) (Table 2). Patients who received repeated S(+)-ketamine reported lower pain scores than those with placebo after awakening and 3 and 6 h later (P 0.05) (Fig. 1). Fewer patients with repeated S(+)-ketamine required additional analgesics than those with placebo (P 0.05) (Fig. 2). Cumulative consumption of additional diclofenac and dextropropoxyphene at 24 h was less after repeated (P < 0.05) and single (P < 0.05) S(+)-ketamine versus placebo (Fig. 3). Postoperative sensory blocks were not different among groups (Table 2). No psychological alterations or side effects related to ketamine use were noted.
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Figure 1. Visual analog scale (VAS) pain scores (A) after awakening, (B) 3 h after awakening, (C) 6 h after awakening, and (D) 24 h after awakening. Columns show the median and range with first and third quartiles and maximum and minimum values per group. *Significant difference between placebo and repeated S(+)-ketamine.
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Figure 2. Patients who required additional diclofenac and dextropropoxyphene. Bars represent the number of patients per group. *Significant difference between placebo and repeated S(+)-ketamine.
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Figure 3. Cumulative consumption of (A) diclofenac and (B) dextropropoxyphene at 24 h after surgery. Columns represent the median and range with first and third quartiles and maximum and minimum values per group. *Significant difference between placebo and repeated S(+)-ketamine; significant difference between placebo and single S(+)-ketamine.
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Discussion
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Our findings show that preincisional and repeated intraoperative S(+)-ketamine added to a combined anesthetic regimen improve pain relief after visceral surgery. After awakening, more patients with repeated S(+)-ketamine felt they were in a better mood. In the postoperative study period, fewer patients with repeated S(+)-ketamine required additional analgesics than those with placebo. The amount of additional analgesics consumed was smaller after repeated S(+)-ketamine than after placebo.
Our data confirm and extend previous work on pain after abdominal surgery with general and epidural anesthesia (11–15). The pain scores noted in our placebo and single S(+)-ketamine group were comparable to those reported for epidural anesthesia alone (11–15). The few trials that have studied IV racemic ketamine, not S(+)-ketamine, however, in this setting cannot be directly compared with our study. We found that repeated S(+)-ketamine decreased postoperative pain, whereas there are discrepancies concerning the effects of repeated racemic ketamine. Thus, racemic ketamine did not reduce postoperative pain when added as a 10-mg preincisional bolus to combined anesthesia for renal surgery that was followed by a postoperative infusion of 10 mg/h for 48 hours (12). The authors concluded that larger ketamine doses would provide increased analgesia. When studied at a larger dose after gastrectomy (13) or renal surgery (14), better pain relief was indeed found after an intraoperative racemic ketamine infusion of 0.5 mg · kg–1 · h–1 preceded by a preincisional bolus of 1 mg/kg (13) or 0.5 mg/kg (14). After adenocarcinoma surgery, racemic ketamine injected as a 0.5 mg/kg preincisional bolus followed by an infusion of 0.25 mg · kg–1 · h–1 reduced morphine needs and caused less residual pain at 6 months after surgery (15). This was not observed when ketamine was used at half the dose.
The reduction in postoperative pain that we hypothesized for multiple S(+)-ketamine is consistent with evidence that ketamine suppressed visceral pain sensitization (16,17). First, S(+)-ketamine reduced NMDA receptor-related injury-induced direct and transferred somatic pain (7–10). Activation of C-fiber nociceptors evokes an NMDA receptor-mediated state of central hyperexcitability in spinal cord neurons, and this accounts for postinjury pain and hyperalgesia (17). Second, S(+)-ketamine probably reduced peripheral and central visceral NMDA and non-NMDA receptor-related nociception (7,18) and enhanced pain-inhibiting systems, such as monoaminergic mechanisms (18). In continuing acute and inflammatory visceral nociception, racemic ketamine was found to reduce pain sensitization and hyperalgesia phenomena (19,20). Third, S(+)-ketamine exerted direct effects on brain areas with pain-perceptive, pain-memory, or pain-inhibitory function (21–23). Positron emission tomography with radiolabeled S(+)-ketamine at doses smaller than those used in our study showed high drug binding in the thalamic regions, the insula, the cortex, and the limbic system (21). Moreover, increased levels of neurotransmitters, such as dopamine, in the ventral striatum and caudate nucleus correlated with positive feelings after S(+)-ketamine in volunteers (23). Because limbic structures and cortico-striatal-thalamic feedback loops overlap with the dopaminergic system, the better mood after repeated S(+)-ketamine may have contributed to pain control in our patients. We did not detect other psychological effects or complications attributable to S(+)-ketamine.
The question to be answered is as follows: what should an intraoperative protocol for effective pain prevention with ketamine look like? As shown in the previously mentioned trials of racemic and R(–)-ketamine (1–3) and as supported by our data, one preincisional injection of even 0.5 mg/kg S(+)-ketamine is insufficient to exert remarkable antinociception that lasts into the postoperative period. In addition to multiple use, S(+)-ketamine must be administered at appropriately large doses to reach the targeted pain reduction. Not surprisingly, a preincisional bolus of S(+)-ketamine 0.5 mg/kg followed by an infusion of 2 µg · kg–1 · h–1 until two hours after anesthesia emergence did not decrease intense somatic pain after remifentanil-based general anesthesia (24). This lack of effect may relate not only to inappropriately small drug doses after cruciate knee ligament repair, but also to remifentanil-induced opioid tolerance and hyperalgesic effects.
There are limitations to this study. We used the lumbar rather than the thoracic approach for epidural catheter placement. Pain could therefore be related to an inappropriately low level of catheter position. However, such a confounding factor should be evenly distributed, and postoperative sensory blocks were similar among our study groups. Moreover, previous studies that used thoracic epidural anesthesia reported insufficient postoperative pain relief as well (13,15). We are aware that rectal diclofenac may not be well absorbed. However, the surgeons considered a nonsteroidal antiinflammatory drug necessary as a rescue analgesic, and its rectal administration is associated with fewer side effects than the oral route. Another limitation of our design is the use of the number of patients who required additional postoperative analgesics as the primary outcome measure in a study concerned with the development of pain sensitization and hyperalgesia. Although we tried to hold the level of postoperative analgesia constant in all patients by continuous infusion of epidural ropivacaine to test our hypothesis, no significant difference between single and repeated S(+)-ketamine was observed. Thus, the power of our study may not have been adequate to detect differences between the two S(+)-ketamine groups.
In conclusion, repeated use of intraoperative S(+)-ketamine as an analgesic adjunct to general and epidural anesthesia improves pain relief after abdominal surgery. The development of combined anesthesia regimens including S(+)-ketamine at adequate use schedules may foster strategies for pain prevention after visceral surgery.
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Acknowledgments
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Supported in part by Pfizer Parke-Davis Pharmaceuticals, Freiburg-Karlsruhe, Germany.
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Accepted for publication November 19, 2003.
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Abstract
Introduction
