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PAIN MEDICINE

The Efficacy of Thoracic Epidural Neostigmine Infusion After Thoracotomy

Yuan-Yi Chia, MD^*, Ting-Hang Chang, MD^*, Kang Liu, MD^*, Huang-Chou Chang, MD, Nai-Hua Ko, RN^*, and Ying-Ming Wang, MD^*

Departments of *Anesthesiology and Chest Surgery, Kaohsiung Veterans General Hospital and School of Medicine, National Yang-Ming University, Taiwan; Institution of Health Care Management, National Sun Yat-Sen University, Kaohsiung, Taiwan

Address correspondence and reprint requests to Ying-Ming Wang, MD, Department of Anesthesiology, Kaohsiung Veterans General Hospital, 386 Ta-Chung First Road, Kaohsiung 813, Taiwan. Address e-mail to ymwang{at}isca.vghks.gov.tw.

	Abstract

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Few anesthesia studies have explored perioperative continuous epidural infusion of neostigmine. We examined such a regimen in thoracotomy patients. Ninety patients were randomized to one of three groups in this double-blind trial. Before anesthesia induction, an epidural catheter was inserted in all patients at T5-8 levels under local anesthesia. Pre-neo patients received bolus 500-µg epidural neostigmine before anesthesia induction followed by infusion of 125 µg/h until the end of surgery. Post-neo patients received epidural saline during the same time periods plus bolus 500-µg epidural neostigmine at end of surgery. Patients in the control group received saline placebo during all three periods. Patients in the neostigmine groups postoperatively received patient-controlled epidural analgesia with morphine 0.02 mg/mL, bupivacaine 0.08 mg/mL, and neostigmine 7 µg/mL. Control patient-controlled epidural analgesia excluded neostigmine. Data were recorded for 6 postoperative days. Daily patient-controlled epidural analgesia consumption (mL) for Pre-neo patients was significantly less than that of post-neo and control group patients for postoperative days 1–6 (at least 10% and 16% less, respectively; P < 0.05). There was a modest decrease in pain intensity on postoperative days 3–6 for pre-neo patients versus other groups (P < 0.05). These results suggest that continuous thoracic epidural neostigmine started before anesthesia provided preemptive, preventive analgesia and an analgesic-sparing effect that improved postoperative analgesia for these patients without increasing the incidence of adverse effects.

	Introduction

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Since the first safety reports on spinal administration of neostigmine methylsulfate were published (1), many researchers have examined intrathecal administration of neostigmine and found that it provides an analgesic effect in postoperative pain models. However, such use is associated with a dose-related incidence of adverse effects; nausea and vomiting are the most troublesome (2–7). Compared with intrathecal administration, coadministration of epidural neostigmine in doses ranging from 1 to 10 µg/kg and local anesthetic result in postoperative analgesia devoid of those adverse effects (8–10). The attractive benefits of epidural neostigmine deserve further evaluation. Several experiments show that an epidural opiate–neostigmine combination via single bolus administration provides an efficient analgesic effect in patients after epidural anesthesia alone or combined with general anesthesia (7,11–13). However, the safety, analgesic effect, and adverse effects of this combination by the epidural route over a longer duration have not been fully evaluated. If such a regimen were devoid of side effects, it would be of interest for postoperative analgesia.

The severe pain that follows thoracotomy puts patients at major risk for pulmonary complications. Effective analgesia and blockade of the perioperative stress response may improve outcome, and epidural analgesia plays a role in reduction of pulmonary complications after thoracic surgery (14).

The current randomized, double-blind, prospective study was designed to examine the postoperative analgesic efficacy of adding neostigmine to a multimodal regimen of patient controlled epidural analgesia (PCEA) in thoracotomy patients, thus validating the concept of preemptive and preventive analgesia for this population.

	Methods

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Approval by the Human Investigation Committee of Kaohsiung Veterans General Hospital was given before implementation of the study. Written, informed consent was obtained from each patient before any research began. Ninety ASA physical status I–III patients who were to undergo thoracotomy were eligible and enrolled. Exclusion criteria included a history of heart disease, hepatic, renal, or psychological disease, allergy to narcotics, and a contraindication to an epidural catheter. Patients were randomly divided into three groups using a table of random digits generated by a computer.

Before the operation, patients were instructed about the use of the visual analog scale (VAS; 0 = no pain, 10 = worst possible pain) and the PCEA device (Pain Management Provider; Abbott Laboratories, Abbott Park, IL). Before the induction of anesthesia, an epidural catheter was placed at the T5-8 intervertebral spaces under local anesthesia with use of a loss of resistance technique, and correct positioning was confirmed by an injection of 3 mL of 2% lidocaine with 1:200,000 epinephrine. For the pre-neo patients, this was followed by an initial 10-mL bolus of 500 µg neostigmine, infusion of 125 µg/h neostigmine during surgery and a 10-mL bolus of normal saline at the end of surgery. Patients in the post-neo group received 10 mL normal saline via epidural catheter before induction of general anesthesia, infusion of normal saline during surgery, and a 500-µg bolus of neostigmine epidurally at the end of the surgery. Patients in the control group received normal saline as placebo three times: before induction of anesthesia, during surgery, and at the end of the surgery. General anesthesia was induced with fentanyl 3 µg/kg, thiopental 5 mg/kg, lidocaine 1.5 mg/kg, and succinylcholine 1.5 mg/kg. Atracurium 0.5 mg/kg/h and isoflurane 1.5%–2.5% were adjusted during surgery to maintain muscle relaxation and depth of anesthesia. Patients' lungs were ventilated with 50% oxygen in air at a tidal volume of 10 mL/kg, with end-tidal CO₂ concentration maintained at 35–40 mm Hg. At the end of surgery, muscle relaxation was reversed by IV administration of neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg for all patients. Intraoperative monitoring included electrocardiography, arterial blood pressure, pulse oximetry, nasopharyngeal temperature, neuromuscular status, measurement of ventilation pressures and volumes, end-tidal CO₂ concentration, and urine output. To avoid intraoperative hypothermia, each patient was placed on a water-warming blanket. An anesthesiologist blinded as to group allocation and not involved in postoperative evaluation or patient contact conducted the entire course of surgical anesthesia. Hemodynamic data such as systolic and diastolic blood pressures and heart rates were recorded as baseline (values on arrival at operating room), preinduction (values at 5 min before induction of anesthesia), induction of anesthesia, tracheal intubation, and maintenance of anesthesia (average values during anesthesia).

At the end of surgery, patients in the pre-neo and post-neo groups received a unified PCEA regimen containing morphine 0.02 mg/mL, 0.08% bupivacaine (0.8 mg/mL), and neostigmine (7 µg/mL); the patients in the control group received a PCEA regimen containing morphine 0.02 mg/mL and 0.08% bupivacaine (0.8 mg/mL). The analgesic mixture was prepared under laminar flow hood in the Department of Pharmacy. The PCEA device was initially programmed to administer a continuous infusion of 2.5 mL/h with a bolus dose of 2.5 mL on demand. The lockout time between boluses was 5 min. Pain intensity during cough or deep breathing (VAS-C) and at rest (VAS-R) was evaluated and recorded with use of a VAS scoring system daily for 6 postoperative days (PDs 1-6). The PCEA infusion rate and bolus volume were titrated according to analgesic effect or occurrence of side effects. If pain relief was unsatisfactory, the background infusion rate and bolus volume were each increased by 0.5 mL. If a patient experienced satisfactory pain relief, the background infusion rate and bolus volume was decreased daily by 0.5 mL. If breakthrough pain followed a decrease, the dose was restored to the previous level. If a patient could not tolerate the pain (VAS-R > 4), we rechecked the epidural insertion site to see whether the epidural catheter migrated and administered 1.0% lidocaine (7 mL) epidurally to ensure that the surgical area was covered by the analgesia field. If this did not result in satisfactory analgesia, we excluded the patient from the study and replaced PCEA with IV PCA. Severe nausea or vomiting was treated with dexamethasone 5 mg, and severe pruritus was treated with chlopheniramine maleate 10 mg IV every 8 h as required. In patients with respiratory depression, we stopped continuous infusion of PCEA and administered intermittent doses of naloxone 40 µg IV. Double blinding was achieved by having our hospital pharmacy personnel prepare epidural infusion bags and PCEA regimens for each patient labeled with the subject's identification number only. Pharmacy personnel who were not involved in patient care or evaluation were allowed to undertake group assignment and randomization, which was achieved using a sequence of random numbers from a computer-generated sequence. The group-assignment code indicating each patient's group assignment was retained by the pharmacy until the conclusion of the study. To ensure patient safety, however, a sealed opaque envelope containing the randomized treatment assignment was kept with each patient in the operating room and intensive care unit to permit immediate unmasking if an emergency made this step necessary.

Each sedation level was recorded according to a 4-point scale (0 = awake and alert; 1 = mildly sedated, easily aroused; 2 = moderately sedated, aroused by shaking; 3 = deeply sedated, difficult to arouse even by shaking). Daily analgesic consumption and side effects such as nausea, emesis, pruritus, respiratory depression, sleep deprivation, or motor block were recorded. Respiratory depression was defined as respiratory rate <10 breaths per minute. Motor block was defined as any objective motor block or complaint of excessive weakness graded according to the 4-point Bromage scale (1 = free movement of legs and feet; 2 = just able to flex knees with free movement of feet; 3 = unable to flex knees but with free movement of feet; 4 = unable to move legs or feet). Patient satisfaction using the VAS score was also recorded at the end of PCEA. All patients were begun with PCEA and followed for at least 6 PDs (PD1-6).

All data are presented as mean ± sd. Parametric data were analyzed using one-way analysis of variance in combination with the Tukey test. Nonparametric data were evaluated using two-factor mixed-design analysis of variance with repeated measurement on one factor, or the Kruskal-Wallis test in combination with the Dunn test. Classification of the number of patients with side effects, the number of patients requesting rescue antiemetic, and patient satisfaction were analyzed using the ² or Fisher's exact tests, as appropriate. A value of P < 0.05 was considered statistically significant. Based on our preliminary data (PD1 VAS-C, 4.5 ± 2.7), power analysis indicates that a sample size of 20 patients per group would yield 80% chance (at = 0.05) of detecting a 30% reduction in pain intensity during activity (VAS-C) on PD1.

	Results

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A total of 90 patients were evaluated. Of these, one patient in the pre-neo group was excluded because of massive perioperative bleeding and wound infection, and one patient in the control group did not complete the study because of transfer for chemotherapy and the addition of nonsteroidal antiinflammatory drugs to a treatment regimen for pain management. This left a sample population of 88 patients in the 3 groups. Demographic data and surgery durations are presented in Table 1. There were no significant between-group differences with respect to age, weight, height, gender, ASA physical status, or surgery duration. Intraoperative hemodynamic data such as systolic and diastolic blood pressures and heart rates are shown in Figure 1; there were no significant differences among groups regarding baseline, preinduction, tracheal intubation, or maintenance data with the exception that maintenance heart rates in the pre-neo group were significantly slower than those in the post-neo and control groups (P = 0.022). All patients were fully awake during postoperative visits and sedation scores were evaluated to be zero with no differences among groups. Pain intensity during cough or deep breathing (VAS-C), at rest (VAS-R), and daily postoperative analgesic regimen consumption (mL) among the three groups are compared in Table 2 and Table 3. There were significantly lower VAS-C and VAS-R scores for the pre-neo group at PD3 (2.8 ± 1.0 and 0.8 ± 0.5, respectively), PD4 (2.3 ± 0.8 and 0.5 ± 0.3, respectively), PD5 (1.8 ± 0.9 and 0.4 ± 0.2, respectively), and PD6 (1.9 ± 0.9 and 0.5 ± 0.2, respectively) compared respectively with not only the VAS-C and VAS-R scores for the post-neo group at PD3 (3.6 ± 1.3 and 1.2 ± 0.4, respectively), PD4 (3.0 ± 1.2 and 0.8 ± 0.2, respectively), PD5 (3.0 ± 1.1 and 1.0 ± 0.3, respectively), and PD6 (2.9 ± 1.2 and 1.0 ± 0.4, respectively) but also the VAS-C and VAS-R scores for the control group at PD3 (3.2 ± 1.2 and 1.4 ± 0.5, respectively), PD4 (3.2 ± 0.8 and 0.9 ± 0.3, respectively), PD5 (2.8 ± 0.9 and 0.7 ± 0.2, respectively), and PD6 (2.6 ± 0.8 and 0.8 ± 0.3, respectively) (P < 0.05, Table 2). Pain intensity at rest scores for all patients were <4, which indicates adequate postoperative pain management.

View larger version (22K): [in this window] [in a new window]   Figure 1. Perioperative hemodynamic profiles. Values are expressed as mean ± sd. SBP = systolic blood pressure; DBP = diastolic blood pressure. * P < 0.05 versus Control group. # P < 0.05 versus post-neo group.

In the pre-neo group, the daily analgesic regimen consumption for PDs1 to 6 were 72.4 ± 6.5, 71.2 ± 6.3 mL, 63.4 ± 6.0 mL, 57.6 ± 5.8 mL, 50.1 ± 5.9 mL, and 44.8 ± 4.9 mL, respectively. In the post-neo group, daily analgesic regimen consumption for PDs1 to 6 were 85.1 ± 7.9 mL, 81.1 ± 6.3 mL, 70.5 ± 6.3 mL, 66.6 ± 5.2 mL, 61.5 ± 5.1 mL, and 60.2 ± 5.2 mL, respectively. In the control group, daily analgesic regimen consumption for PDs1 to 6 were 87.7 ± 7.5 mL, 85.3 ± 7.3 mL, 89.9 ± 7.2 mL, 83.3 ± 7.8 mL, 75.1 ± 6.9 mL, and 70.1 ± 6.8 mL, respectively. The daily analgesic regimen consumption in the pre-neo group was significantly less than in the other 2 groups over PDs1-6 (P < 0.05, Table 3), and the dose consumed in the post-neo group was significantly smaller than that of the control group over PDs3-6 (P < 0.05, Table 3).

The incidence of side effects such as nausea, vomiting, pruritus, dizziness, and satisfaction when PCEA was ended is presented in Table 4. The intervention groups (pre-neo and post-neo groups) had a more frequent incidence of vomiting and nausea than the control group; however, there was no significant difference regarding those side effects and satisfaction among the 3 groups for PDs1-6. Two patients in the post-neo group and one patient in the pre-neo group requested treatment for severe vomiting. One patient in the pre-neo group and one in the control group who could not tolerate pruritus asked for treatment. There was no significant difference regarding the number of patients requesting treatment for vomiting or pruritus. No patient experienced motor block or respiratory depression during the postoperative period.

	Discussion

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The results of the current study indicate that continuous epidural neostigmine infusion started before induction of anesthesia and extended into the postoperative period (pre-neo group) provided preemptive and preventive analgesia and modestly decreased pain intensity during the postoperative period compared with postoperative epidural neostigmine infusion and saline placebo infusion (post-neo and control groups, respectively). Postoperative epidural neostigmine infusion via PCEA (post-neo group) decreased postoperative daily analgesic consumption with similar pain intensity compared with the control group.

Reviews of clinical studies regarding the significance of preemptive analgesia are controversial. An earlier definition of preemptive analgesia, prevention of establishment of central sensitization caused by incision injury, leads to a concept that preemptive analgesia is not clinically significant (15,16), and some authors have concluded that the definition of preemptive analgesia is the major source of controversy related to its clinical relevance (17). Two studies have suggested that central sensitization caused by postoperative inflammatory injuries makes the preoperative versus postoperative study design inadequate for assessment of clinical significance of preemptive analgesia (17,18). This would suggest that the previous definition of preemptive analgesia is too restrictive. Kissin (17,19) introduced the term "preventive analgesia" to emphasize the fact that central sensitization is induced by noxious preoperative and postoperative inputs and has been used to describe a reduction in postoperative pain intensity, analgesic consumption, or both, of the target drug. The aim of preventive analgesia is to reduce central sensitization that occurs from noxious inputs across the entire perioperative period when compared with placebo and not just from those initiated by incision (20). These concepts suggest a possible study design: effective analgesia starts before incision, covers both the period of surgery and the postoperative period, and provides short-term and/or long-term benefits in postoperative outcomes. Our current study showed that antinociceptive treatment with continuous epidural neostigmine started before noxious stimulation and extended into the postoperative period produced effective analgesia, resulted in better pain outcomes (reduced pain intensity and analgesic consumption) comparing the pre-neo and post-neo groups (preemptive analgesia) or comparing the pre-neo and control groups (preventive analgesia). The addition of neostigmine 7 µg/mL in the multimodal analgesic mixture also produced an analgesic-sparing effect, which reduced the analgesic mixture consumption between the post-neo and control groups.

The effective dose of epidural neostigmine remains unclear because of inconsistencies among previous studies. For patients after arthroscopy, coadministration of epidural neostigmine 1 µg/kg with lidocaine 85 mg produced effective analgesia over 5 hours (8). The same group also demonstrated that epidural neostigmine 1 µg/kg combined with intrathecal bupivacaine decreased postoperative analgesic consumption and pain intensity (9). However, in patients who underwent abdominal hysterectomy, coadministration of epidural neostigmine 5 µg/kg and bupivacaine did not produce effective analgesia postoperatively, whereas coadministration of epidural neostigmine 10 µg/kg and bupivacaine provided effective analgesia (10). These findings raise the possibility that the effective dose of epidural neostigmine might vary with the type of surgery, the dose being larger for more extensive and painful surgical procedures than for minor ones. The thoracotomy incision is considered one of the more painful incisions; the pain is mainly a result of the cutting of the muscles between the ribs and spreading the ribs apart. After surgery, every breath the patient takes expands the chest and spreads the incision to cause severe, painful sensations. Hence, in the current study, we evaluated epidural infusion of neostigmine in patients after thoracotomy procedures: patients in the pre-neo group received a modest single-dose of epidural neostigmine (500 µg, which was estimated to be around 8–10 µg/kg) before induction of anesthesia, followed by an infusion of 125 µg/h (estimated to be around 2 µg · kg^–1 · h^–1) epidural neostigmine.

VAS-C and VAS-R scores on PDs1 and 2 were not significantly different among the 3 groups, because patients in the post-neo and control groups consumed significantly more analgesics to reduce pain intensity. Interestingly, on PDs3-6, though there were significantly more analgesics consumed, VAS-C and VAS-R scores in the post-neo and control groups were still significantly higher than those of the pre-neo group. However, patients in the post-neo and control groups did not titrate the supplemental analgesic regimen to lower levels of VAS scores, which might suggest that these differences in pain intensity are not clinically relevant. Consistently, most VAS scores were below 3. Taken together, the lack of difference in pain intensity among groups on PDs1-2 and clinically nonrelevant reduction in pain intensity in the pre-neo group on PDs3-6, may reflect an extensive painful surgical procedure and the addition of neostigmine should be a little less in light of these facts.

In the post-neo group, epidural neostigmine infusion started at the end of surgery reduced daily analgesic consumption on PDs 3 to 6 compared with the control group. Even though the analgesic consumption of the post-neo group was not statistically significant on PDs 1 and 2 compared with the control group, a trend towards analgesic sparing was noted (85.1 ± 7.9 and 81.1 ± 6.3 mL on PDs 1 and 2, compared with 87.7 ± 7.5 and 85.3 ± 7.3 mL in the control group, respectively). The mechanism for these findings is unclear, but the lack of a statistically significant analgesic-sparing effect on PDs 1 and 2 might reflect the small dose of epidural neostigmine, the extensive painful surgical procedure, or both. These results indicate that postoperative epidural neostigmine in combination with epidural bupivacaine and fentanyl provides an approximately 13.5% postoperative bupivacaine- and fentanyl-sparing effect. Previous studies evaluating coadministration of epidural neostigmine/morphine or neostigmine/lidocaine for postoperative pain in patients after orthopedic surgery produced similar results, with demonstration of an analgesic-sparing effect (8,21). However, pain intensity between our post-neo and control groups was not statistically significant. Those data suggest that continuous epidural neostigmine started after surgery neither prevents nor decreases establishment of central hypersensitivity (thus failing to decrease postoperative pain intensity for our post-neo group compared with the control group), but it still provides an analgesic-sparing effect. In animal research, it has been suggested that blockade for a successful reversal of established hypersensitivity should be stronger in intensity and longer in duration than a preemptive effect to prevent establishment because the intensity of afferent input for reinitiation of central hypersensitivity is less than that for its initiation (22).

Many experiments indicate that spinally administered neostigmine increases arterial blood pressure and heart rate, an effect possibly mediated by activating preganglionic sympathetic neurons (23,24). In 2 healthy volunteers, intrathecal injection of 750 µg neostigmine was associated with increased arterial blood pressure and heart rate; however, the mechanism for these increases is unknown (1). Interestingly, in the current study, maintenance heart rates in the pre-neo group were slower than in the post-neo and control groups. In an animal research study, modest bradycardia was observed within 2 to 3 days and sustained over a 28-day study course in dogs after initiation of 4 mg/4 mL/day chronic intrathecal neostigmine infusion (25). Lauretti et al. (12) reported that 200 µg intrathecal neostigmine induced bradycardia for 4 to 5 hours in 2 patients, which could be explained by central cholinergic activation caused by cephalic spread of neostigmine. In the current study, the slower maintenance heart rate during continuous epidural neostigmine infusion (125 µg/h) might have been caused by cephalic spread of epidural neostigmine, via activation of the central cholinergic system with resultant slower maintenance heart rate. It is also possible that epidural neostigmine was reabsorbed by the epidural venous plexus into systemic blood flow, leading to slower heart rates during maintenance of anesthesia. However, the reduction in heart rate was within 15% of the baseline heart rate and thus clinically acceptable and harmless (Fig. 1).

Nausea and vomiting occurred in a dose-dependent manner after intrathecal neostigmine in healthy volunteers; this was thought to be the most likely bothersome side effect that could limit the utility of spinal neostigmine in clinical practice. This side effect was suggested to be secondary to cephalic spread of intrathecal neostigmine (1). However, previous studies examining lumbar epidural administration of neostigmine showed that epidural neostigmine seemed to avoid or attenuate these side effects (8,10). Our results are in agreement with those data, demonstrating that thoracic infusion of epidural neostigmine was not associated with an increased incidence of postoperative nausea and vomiting. Sedation, which was a major concern in the phase I study (safety assessment) of intrathecal neostigmine (150–750 µg) in healthy volunteers (1), was rarely assessed in previous clinical studies of epidural or intrathecal neostigmine alone or combined with morphine or bupivacaine (2,5,8–10,12). One recent study demonstrated that epidural neostigmine (75–300 µg) resulted in dose-independent mild sedation and extended into the postoperative period for 24 hours in women undergoing cesarean delivery, a phenomenon that was attributed to increased central cholinergic receptor stimulation (26). However, our results found that all patients were fully awake and alert when visited, even patients who received prolonged continuous epidural neostigmine infusion. The mechanism accounting for these discrepancies is unknown, but a relatively small dose of postoperative epidural neostigmine infusion and tolerance of the central nerve system to neostigmine (a phenomenon that has been observed after chronic administration of intrathecal neostigmine in rats) may account for the absence of this adverse effect (27). In one study involving prolonged continuous infusion of epidural neostigmine coadministered with local anesthetic, motor block became a concern for patients intended to have early ambulation; however, multimodal analgesia lessened the severity of this side effect (28). It has been demonstrated in healthy volunteers that intrathecal neostigmine alone (50–750 µg) induces dose-related motor weakness, an effect assumed to be attributable to direct actions on motor-neuron outflow (1). Two previous studies have also reported that the addition of neostigmine 50 µg to bupivacaine for spinal anesthesia causes prolonged sensory and motor blockade (3,29). However, a recent study found that epidural neostigmine (250–750 µg; 3–10 µg/kg) combined with sufentanil provides analgesia without significant motor impairment in early labor (30). Patients in both the pre-neo and post-neo groups of our study showed no motor block or weakness during epidural neostigmine infusion extended over 6 postoperative days. Our results seem to suggest that continuous thoracic epidural administration of small-dose neostigmine has the benefit of minimizing the risk of motor block. Overall, no significant differences in the incidence of nausea, vomiting, sedation, or motor block were seen among the three groups. However, the lack of differences in adverse effects among groups might also have been a result the smaller sample size with respect to these side effects.

In conclusion, our results suggest that preoperative use of epidural neostigmine for thoracotomy patients followed by continuous infusion during surgery with extension into the postoperative period (e.g., 6 days) provides preemptive and preventive analgesia effects on postoperative pain intensity and provides an analgesic-sparing effect on PCEA consumption, with both effects achieved without increasing the incidence of adverse effects.

	Footnotes

 
Supported, in part, by Research Program VGHKS93-07 at Kaohsiung Veterans General Hospital.

Accepted for publication August 19, 2005.

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