Abstract

Objective(s)

Previous studies have shown that preincisional epidural morphine, bupivacaine, and ketamine combined with epidural anesthesia (EA) and general anesthesia (GA) provided pre-emptive analgesia for upper abdominal surgery. Recent studies reported that ultralow-dose naloxone enhanced the antinociceptive effect of morphine in rats. This study investigated the benefits of preincisional and postoperative epidural morphine + ropivacaine + ketamine + naloxone (M + R + K + N) treatment for achieving postoperative pain relief in upper abdominal surgery.

Methods

Eighty American Society of Anesthesiology I–II patients scheduled for major upper abdominal surgery were allocated to four groups in a randomized, single-blinded study. All patients received combined GA and EA with a continuous epidural infusion of 2% lidocaine (6–8 mL/h) 30 minutes after pain regimen. After GA induction, in Group I, an epidural pain control regimen (total 10 mL) was administered using 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg; M + R); in Group II, 1% lidocaine 8 (mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg; M + R + K); in Group III, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + naloxone (2 μg; M + R + N); and in Group IV, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg) + naloxone (2 μg; M + R + K + N), respectively. All patients received patient-controlled epidural analgesia (PCEA) with different pain regimens to control subsequent postoperative pain for 3 days following surgery. During the 3-day period following surgery, PCEA consumption (mL), numerical rating scale (NRS) score while cough/moving, and analgesic-related adverse effects were recorded.

Results

Total PCEA consumption for the 3-day observation period was 161.5 ± 17.8 mL, 103.2 ± 21.7 mL, 152.4 ± 25.6 mL, and 74.1 ± 16.9 mL for Groups I, II, III, and IV, respectively. (p < 0.05). The cough/moving NRS scores were significantly lower in Group IV patients than Groups I and III patients at 4 hours, 12 hours, and on Days 1 and 2 following surgery except for Group II (p < 0.05).

Conclusion

Preincisional and postoperative epidural M + R + K + N treatment provides an ideal postoperative pain management than preincisional and postoperative epidural M + R, M + R + K, and M + R + N treatments in upper abdominal surgery.

Keywords

epidural analgesia; ketamine; naloxone; postoperative pain; upper abdominal surgery;

1. Introduction

Tissue damage during surgery generates ongoing sensory signals and affects central nervous system function, while the response of nociceptive neurons in the spinal cord further complicates postoperative pain management. Inadequately treated pain may result in detrimental physiological, psychological, economic, and social adverse effects. Early studies proposed that adequate prevention of nociceptive neuron sensitization in the spinal cord could significantly enhance postoperative pain relief, thereby resulting in a lower analgesic requirement than administering analgesia after surgery.1, 2, 3

Upper abdominal surgeries lead to severe abdominal pain, which if treated inadequately, can cause shallow breathing, atelectasis, retention of secretions, and patients to refuse physiotherapy. This increases the incidence of postoperative morbidity and leads to delayed recovery.⁴ Postoperative epidural analgesia for major upper abdominal surgery provides significant benefits, including superior analgesia and reduced pulmonary dysfunction.⁵ The existence of opioid receptors in the spinal cord permits the use of epidural morphine (National Bureau of Controlled Drugs, Department of Health, R.O.C.) to control various pain conditions.6, 7 When ropivacaine (Nang Kuang Pharmaceutical CO., LTD, R.O.C.) is combined with morphine, the duration and efficacy of analgesia are greater.⁸ The N-methyl-d-aspartate (NMDA) antagonist ketamine (United Biomedical, Inc., Asia) not only attenuates peripheral afferent noxious stimuli, but also prevents the central sensitization of spinal neurons.9, 10, 11 Epidural administration of ketamine not only potentiated the analgesic effect of morphine,¹² but also provided a pre-emptive analgesic effect on patients who underwent total knee joint replacement.² Our previous study showed that preincisional epidural morphine, bupivacaine, and ketamine in combination with epidural anesthesia (EA) and general anesthesia (GA) provided pre-emptive analgesia for upper abdominal surgery.¹³ Interestingly, recent studies have reported that ultralow-dose naloxone (Genovate Biotechnology CO., LTD, R.O.C.) enhanced the antinociceptive effect of morphine in rats.14, 15, 16 In this study, the epidural analgesic effect of a four-drug pain regimen [morphine + ropivacaine + ketamine + naloxone (M + R + K + N)] was investigated on major upper abdominal surgery.

2. Methods

This study was approved by the Ethics Committee (TSGHIRB No: 517) of Tri-Service General Hospital, Taipei, Taiwan (Chairman, Professor Chih-Shung Wong) on December 23, 2005. All patients provided written informed consent before being enrolled.

From June 2006 to October 2007, 80 American Society of Anesthesiology I–II patients undergoing upper abdominal surgery with hepatic resection were selected for a randomized, single-blind experiment. Patients who had received opioids or nonsteroidal anti-inflammatory drugs within 1 week of surgery were excluded from participation. All the selected 80 patients were randomly divided into four groups using a random number table and they remained in the study for the entire observation period. One day before surgery, an epidural catheter (Smiths Medical Australasia Pty. Ltd., Australia) was inserted at T₈–T₁₀ and advanced 5 cm into the epidural space. A test dose of 3 mL of 2% lidocaine (AstraZeneca, Sweden) containing epinephrine (5 μg/mL, China Chemical & Pharmaceutical Co., Ltd., R.O.C.) was also administered to rule out intrathecal or intravascular misplacement. Patients were also instructed in the use of the numerical rating scale (NRS; 0 = no pain, 10 = greatest pain) and the patient-controlled epidural analgesia (PCEA) device (Hospira Costa Rica Ltd., Costa Rica).

On the day of surgery, GA was induced with fentanyl (2 μg/kg, National Bureau of Controlled Drugs, Department of Health, R.O.C.), thiopental (3–5 mg/kg, Shinlin Sinseng Pharmaceutical Co., Ltd, R.O.C.), and succinylcholine (1.5 mg/kg, Shinlin Sinseng Pharmaceutical Co., Ltd, R.O.C.) and maintained with atracurium (Genovate Biotechnology CO., LTD, R.O.C.) and isoflurane (AESICA QUEENBOROUGH LIMITED, UK) in oxygen (0.5 L/min). Monitoring included pulse oximetry, electrocardiogram, end-tidal CO₂, anesthetic gases (5330 Agent Monitor, Ohmeda), noninvasive blood pressure, central venous pressure, and intra-arterial pressure. After GA induction, the epidural pain regimens (total 10 mL) were prescribed in each group as follows: Group I, an epidural pain control regimen was administered using 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg; M + R); Group II, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg; M + R + K); Group III, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + naloxone (2 μg; M + R + N); and Group IV, 1% lidocaine (8 mL) + morphine (2 mg) + ropivacaine (20 mg) + ketamine (20 mg) + naloxone (2 μg; M + R + K + N), respectively (Table 1). The EA with a continuous epidural infusion of 2% lidocaine (6–8 mL/h) 30 minutes after preincisional epidural pain regimen was prescribed. No additional intravenous opioids or ketamine was given during the operation. The level of anesthesia was considered adequate if the heart rate and arterial blood pressure remained within 20% of the preinduction values. Furthermore, isoflurane was adjusted to keep the auditory evoked potential index (AEP version 1.4, Danmeter, Odense, Denmark) between 15 and 25 during maintenance of anesthesia. All patients received different PCEA regimens according to different groups to control subsequent postoperative pain for 3 days following surgery. PCEA morphine in 0.1% ropivacaine (0.05 mg/mL, 15-minute lockout interval, and no 4-hour limit) was also available as needed for any breakthrough pain. The PCEA solution contents and the setting of bolus amount in each group are shown in Table 1.

Table 1. Study protocol used for testing effects of pre-emptive analgesia and postoperative PCEA solution contents.

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Patient response was observed for 3 days following the surgery. Total PCEA consumption (mL) was recorded for each patient. Patients provided NRS while resting and coughing/moving. Analgesic-associated adverse effects (such as nausea, vomiting, pruritus, urinary retention, and respiratory depression) were recorded by both patients and the nurse in-charge every 24 hours. Respiratory depression was defined as a respiratory rate less than 10 breaths/min. Pruritus was treated with chlorpheniramine maleate (10 mg, intravenously, Sintong Taiwan Biotech CO., LTD, R.O.C.), and metoclopramide (10 mg, intravenously, SANOFI WINTHROP INDUSTRIE, France) was given for nausea or vomiting.

Patient characteristics were expressed as means ± standard deviation, number, or median with range (Table 2). Postoperative pain evaluation values were not normally distributed and median values are presented. The four groups were then compared using analysis of variance to determine whether the M + R + K + N procedure had a beneficial effect on postoperative pain relief. Data on PCEA consumptions and NRS among groups in the following periods were analyzed for each measure using analysis of variance with repeated measures. The Bonferroni procedure was conducted for multiple comparisons between groups in different time points. The level of statistical significance was determined as p < 0.05. Statistical analysis was performed using SigmaStat 3.5 for Windows.

Table 2. Characteristics of study patients.

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3. Results

The demographic characteristics were comparable in the four groups (Table 2). Total PCEA consumption for the 3-day observation period were 161.5 ± 17.8 mL, 103.2 ± 21.7 mL, 152.4 ± 25.6 mL, and 74.1 ± 16.9 mL for Groups I, II, III, and IV, respectively (p < 0.05, Figure 1A). Furthermore, total PCEA consumption for the 3-day observation period was significantly lower in Group II than Groups I and III following surgery (p < 0.05, Figure 1A). Data on PCEA consumptions among groups in each following time point were shown as mean ± standard deviation (Figure 1B). Group IV patients had significantly lower PCEA consumption than Groups I, II, and III at 4 hours and on Day 1 following surgery (p < 0.05, Figure 1B). Group II and IV patients had significantly lower PCEA consumption than Groups I and III at 12 hours and on Days 2 and 3 following surgery (p < 0.05, Figure 1B). There was no significant difference between Groups II and IV at 12 hours and on Days 2 and 3 following surgery in PCEA consumption. Figure 1 shows the postoperative PCEA consumption in the four groups. The cough/moving NRS were significantly lower for Group IV patients than Groups I and III patients at 4 hours, 12 hours, and on Days 1 and 2 following surgery except for Group II (p < 0.05, Table 3). There were no significant differences in the resting NRS for the four groups in the observed period following surgery. However, the cough/moving NRS showed no significant differences for the four groups on Day 3 following surgery. No serious analgesic-related adverse effects were observed in any of the patients. None of the patients suffered nausea and vomiting during the 1^stpostoperative day. Furthermore, none of the patients suffered from vomiting/dizziness/itching in the following 3 days after surgery.

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Figure 1. (A) Total postoperative patient-controlled epidural analgesia (PCEA) consumption (mL) in the four groups. Data on total PCEA consumption are shown as mean ± SD. * p < 0.05: Group II compared with Group I; ** p < 0.05: Group III compared with Group II; *** p < 0.05: Group IV compared with Groups I, II, and III; (B) PCEA consumption (mL) in the four groups. Data on PCEA consumption are shown as mean ± SD. *p < 0.05: Group II compared with Group I; ** p < 0.05: Group III compared with Group II; *** p < 0.05: Group IV compared with Groups I and III; **** p < 0.05: Group IV compared with Groups I, II, and III.SD = standard deviation.

Table 3. Postoperative coughing or moving numerical rating scale scores in the four groups.

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4. Discussion

We first demonstrated that preincisional and postoperative epidural morphine, ropivacaine, ketamine, and naloxone treatment provides an ideal analgesic therapy, consuming less postoperative PCEA amount and producing less postoperative pain than M + R, M + R + K, and M + R + N treatments in patients receiving major upper abdominal surgery. The result suggested that ultralow-dose naloxone enhanced the antinociceptive effect of morphine and ketamine in clinical patients. In addition, patients treated with ketamine (M + R + K) had significantly lower PCEA consumption and better pain relief than patients in groups M + R and M + R + N.

Recent studies reported that intrathecal ultralow-dose naloxone enhanced the antinociceptive effect of morphine in neuropathic pain rats.14, 15, 16 Tsai et al¹⁴showed that pertussis toxin injection induced thermal hyperalgesia and a significant increase of global histone methylation in the spinal cords. Intrathecal morphine alone did not affect the thermal hyperalgesia and global histone methylation. By contrast, intrathecal administration of ultralow-dose naloxone plus morphine significantly attenuated the pertussis toxin-induced thermal hyperalgesia and downregulated the global histone methylation. Intrathecal ultralow-dose naloxone enhances the antinociceptive effect of morphine by enhancing the reuptake of excitatory amino acids (EAAs) from the synaptic cleft in the spinal cord of partial sciatic nerve-transected rats.¹⁵ Intrathecal ultralow-dose naloxone increases the antihyperalgesic and antiallodynic effects of morphine in the same neuropathic pain rats, possibly by reducing tumor necrosis factor-α and its receptor (TNFR1) expression, and EAAs concentrations in the spinal dorsal horn.¹⁶ Accordingly, intrathecal ultralow-dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions. Meanwhile, Lin et al¹⁷ showed that coadministration of intrathecal ultralow-dose naloxone attenuated morphine tolerance in rats via attenuation of NMDA receptor neurotransmission and suppression of neuroinflammation in the spinal cords. Intrathecal co-infusion of ultralow-dose naloxone (15 pg/h) with morphine attenuated tolerance development; reversed glutamate transporters expression; inhibited the NMDA receptor NR1 subunit expression and phosphorylation, protein kinase C gamma expression, and glial cell activation; and suppressed the morphine-evoked EAAs release. Furthermore, previous studies reported that ultralow-dose naloxone intravenous infusion (0.25 μg/kg/h) significantly reduced postoperative opioid requirements in open colorectal surgery and hysterectomy.18, 19 In our study, adding epidural naloxone (0.5 μg/mL) not only significantly reduced total PCEA consumption for the 3-day observation period but also provided an ideal postoperative analgesic therapy. However, in our results shown in Figure 1 and Table 3, there were no significant differences between the PCEA consumptions and pain intensity between the morphine group (Group I) and the morphine/naloxone group (Group III). Therefore, the better results between groups may be based on whether or not ketamine is added to the regimen, but not based on naloxone alone. It is also possible that naloxone may potentiate the analgesic effects only in the existence of ketamine.

The NMDA receptors were shown to play an important role in the modulation of nociceptive inflammation in the spinal cord.9, 10 In humans, surgical trauma may activate the NMDA receptors that alter sensory processing and amplify and prolong postoperative pain.20, 21 Previous studies had showed that preincisional dextromethorphan, an NMDA antagonist, provided pain relief after surgeries.22, 23, 24, 25, 26 Roytblat et al²⁷ showed that low-dose ketamine (0.15 mg/kg) given intravenously before surgical stimulation in combination with GA produced better postoperative pain relief and reduced morphine requirements, compared with GA alone. Tverskoy et al²⁸ also demonstrated that fentanyl and ketamine pre-emptively decreased postoperative wound hyperalgesia. Furthermore, Chia et al²⁹demonstrated that adding ketamine in a multimodal PCEA regimen improves postoperative analgesia. Choe et al³⁰ reported that better postoperative analgesia was observed in patients who received preincisional epidural morphine plus ketamine compared with patients receiving morphine and ketamine after surgical incision. We also showed that preincisional epidural morphine, bupivacaine, and ketamine provided pre-emptive analgesia for upper abdominal surgery.¹³ In our study, patients who received ketamine (Groups II and IV) had significantly lower PCEA consumption and cough/moving NRS. Therefore, ketamine played an important role in postoperative pain management.

Continuous EA with local anesthetics blocked the sensory input from surgical stimuli and provided adequate pain relief.31, 32 Morphine activates the opioid receptors and suppresses the initial response of dorsal horn nociceptive neurons and C-fiber stimulation. Ketamine, via the NMDA receptors, affects the potentiation of responses from repeated surgical stimulation.¹³ Ultralow-dose naloxone enhanced the antinociceptive effect of morphine.14, 15, 16 Coadministration of ultralow-dose naloxone with morphine attenuated NMDA receptor neurotransmission and suppressed neuroinflammation in the spinal cords. As our study, this epidural pain control regimen (M + R + K + N) may produce an ideal analgesic effect for postoperative pain.

There were some limitations in our study. First, we merely included the surgical patients receiving hepatic resection. Further studies on surgical patients receiving different surgeries are needed. Second, we did not assess the effect of pain regimens on postoperative hyperalgesia. We only focused on the evaluation of pain at rest and during coughing/moving. Third, we did not measure the concentration of EAAs in the cerebrospinal fluid and other biomarkers in spinal cord tissues to investigate the mechanisms underlying enhancement of the antinociceptive effect of morphine and ketamine by ultralow-dose naloxone administration in humans. Fourth, the concentrations of ketamine and naloxone should be investigated further. The concentration of epidural ketamine in the PCEA formula was based on our previous study.¹³ The ultralow-dose naloxone in the previous studies was intrathecal injection in animals or intravenous infusion in humans. In our study, the concentration of epidural naloxone was 0.5 μg/mL and the total consumption of naloxone was <100 μg in 3 days. Therefore, the concentration or dose of naloxone might be optimal or suboptimal for postoperative pain management and further investigation is needed. Finally, the use of epidural ketamine and naloxone was off-label.

In conclusion, preincisional and postoperative epidural pain control regimen with morphine, ropivacaine, ketamine, and ultralow-dose naloxone provided ideal analgesic management by significantly lowering PCEA consumption and pain intensity before Day 1 in patients after upper abdominal surgery. Furthermore, morphine, ropivacaine, and ketamine (without naloxone) also provided adequate postoperative pain relief following upper abdominal surgery.

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgments

This work was supported by a grant from National Science Council (NSC 94-2314-B-016-021) of Taiwan, Republic of China.