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Anesth Analg 2002;95:1698-1701 © 2002 International Anesthesia Research Society
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Abstract |
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In this study, we examined the side effects and analgesia of the combination of epidural neostigmine and morphine in patients undergoing orthopedic surgery. Sixty patients undergoing knee surgery were divided into four groups. The intrathecal anesthetic was 15 mg of bupivacaine. The epidural test drug was diluted in saline to a final volume of 10 mL. The control group received saline as the epidural test drug. The morphine group received 0.6 mg of epidural morphine. The neostigmine group (NG) received 60 µg of epidural neostigmine. The morphine/neostigmine group received 0.6 mg of epidural morphine combined with 60 µg of epidural neostigmine. The groups were demographically the same and did not differ in intraop- erative characteristics. The visual analog scale score at first rescue analgesic and the incidence of adverse effects were similar among groups (P > 0.05). One patient from the NG complained of intraoperative nausea, closely related to spinal hypotension. Postoperatively, two patients from the NG had vomited once. The time (min) to first rescue analgesic was longer in the morphine/neostigmine group (
11 h) compared with the other groups (P < 0.05). The analgesic consumption (number of analgesic administrations in 24 h) was larger in the control group compared with the other groups (P < 0.05). IMPLICATIONS: The combination of epidural morphine and epidural neostigmine resulted in postoperative analgesia (11 h) devoid of side effects, being an alternative analgesic technique in the population studied.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a series of clinical studies using spinal anesthesia, intrathecal neostigmine resulted in an analgesic effect and a dose-related incidence of adverse effects in a model of postoperative pain using the intrathecal anesthetic technique, with nausea and vomiting being the most troublesome (1–5). In a model of postoperative pain, the combination of both intrathecal morphine and neostigmine resulted in analgesia, however this is associated with a frequent incidence of nausea and vomiting (6). In addition, Hood et al. (7) have demonstrated that intrathecal neostigmine enhanced side effects, such as nausea, after an IV opioid administration.
Compared with the intrathecal administration, epidural neostigmine doses ranging from 1–10 µg/kg resulted in postoperative analgesia devoid of adverse effects (8–10). Although the analgesic efficacy of an intrathecal opiate/neostigmine combination has been demonstrated (6,7,11,12), analgesia and adverse effects of both drugs by the epidural route of administration have not been evaluated in acute pain and, if devoid of side effects, would be of interest in postoperative analgesia.
The present study was designed to examine postoperative analgesia and the adverse effects of epidural neostigmine and morphine in a randomized, blinded trial in patients undergoing orthopedic surgery.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Ethical Committee of the University of São Paulo’s Teaching Hospital, Ribeirão Preto, approved the study protocol. After informed consent, 60 ASA physical status I and II patients scheduled for knee orthopedic procedures were randomized to one of four groups (n = 15) and prospectively studied using a placebo-controlled, double-blinded design to examine analgesia and adverse effects, mainly nausea and vomiting. The concept of visual analog scale (VAS), which consisted of a 10-cm line with 0 equaling no pain at all or no nausea and 10 equaling the worst possible pain or worst possible nausea, was introduced before surgery. The same team of surgeons operated on all patients.
Patients were premedicated with IV midazolam 0.05–0.1 mg/kg in the holding room. Hydration consisted of 10 mL/kg of lactated Ringer’s solution before surgery and 10 mL · kg-1 · h-1 after combined spinal anesthesia. The randomization was computer generated. Combined spinal/epidural anesthesia was performed in the operating room at the L3-4 or L2-3 interspaces with the patient in the sitting position. The epidural test drug was diluted in saline to a final volume of 10 mL. The control group (CG) received saline as the epidural test drug. The morphine group (MG) received 0.6 mg of epidural morphine. The neostigmine group (NG) received 60 µg of epidural neostigmine. The morphine/neostigmine group (M/NG) received 0.6 mg of epidural morphine combined with 60 µg of epidural neostigmine. The same anesthesiologist did the spinal punctures. The epidural test drug was injected slowly as a bolus. Immediately after the epidural injection, 15 mg of hyperbaric bupivacaine (3 mL) was injected at 1 mL/7 s through a 25- or 27-gauge intrathecal needle in the interspace below. Patients were placed supine after spinal injection.
The decision about the dose of epidural neostigmine was based on previous experience where 1 µg/kg of neostigmine (or 60 µg in a mean of a 60-kg patient) had been used in a similar population (8). The small epidural dose of morphine was defined based on the surgeon’s impression of a frequent incidence of urinary retention after more usual doses, such as 2 mg of morphine. We were focusing on getting the benefit of the combination of small doses of both drugs to avoid adverse effects but with the benefit of long-term postoperative analgesia.
Intraoperative sensory loss assessment included the pinprick test at 5 and 10 min after the injection. Blood pressure was noninvasively monitored every 5 min throughout surgery, and heart rate and oxyhemoglobin saturation (SpO2) were continuously monitored throughout surgery. A decrease in mean arterial blood pressure more than 15% less than preanesthetic baseline values was treated by incremental doses of ephedrine 5 mg IV. Decreases in heart rate less than 50 bpm were treated with incremental doses of atropine 0.25 mg IV. Intraoperative nausea was scored by the patient using the 10-cm VAS. The number of patients having nausea (of any degree) or vomiting at any point during surgery was noted. A nausea score more than 2 of 10 at any time or vomiting during the study were treated with metoclopramide 10 mg IV, followed by droperidol 0.5 mg IV if required.
Postoperative assessment included pain scores at the time of first rescue analgesic and 24 h after the spinal puncture, adverse effects (focusing on nausea and vomiting), and the duration of motor block, which was measured from the time of anesthetic injection until the time to reach a Bromage 2 score. Duration of effective analgesia was measured as time from the spinal drug administration to the patient’s first request for analgesic administration in the recovery room, recorded in minutes. The VAS at the time of first rescue analgesic medication was measured using the 10-cm VAS. Ketoprofen (100 mg IV) at 8-h intervals was available at patient request. If a patient still complained of pain (VAS 
4 cm 30 min after the ketoprofen administration), 1 g of IV dipyrone was available at a minimum of 6-h intervals. The 24-h VAS pain score reflected the patient’s overall impression during the 24 h after spinal injection.
The number of subjects per group (n = 15) was based upon previous preliminary data, which was based on the incidence of nausea after a known dose of spinal neostigmine. We hypothesized that 60 µg of epidural neostigmine would result in a similar incidence of nausea to 6 µg of intrathecal neostigmine. We further hypothesized that the combination of both would triple the time to first rescue analgesic when compared with the CG without increasing the incidence of emesis. If we estimated a SD for this prospective power analysis of 40% and an 
value of 0.05, these assumptions would require six patients in each group to see the increase in the time to the first rescue analgesic. To further increase the power, we elected to observe 15 patients in each group. Groups were compared for demographic data (age, weight, and height) by one-way analysis of variance. Incidence of adverse events, sex, and site of primary disease were compared among groups by 
2 analysis corrected for multiple tests (P < 0.05/4). VAS scores were compared among groups by two-way analysis of variance for repeated measures. Tukey Honest analysis was applied to correct P values. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The four groups showed no differences in sex, ASA status, weight, age, and height (P > 0.05; Table 1). No failure in the spinal anesthesia was noted. The distribution of the types of surgical procedures was similar among groups. Two patients in the CG, four in the MG, three in the NG, and five in the M/NG underwent knee arthroplasty. The others underwent knee arthroscopy/meniscus repair (P > 0.05). The surgical time, anesthetic time, the level to pinprick at 5 and 10 min, and intraoperative ephedrine consumption were also similar among groups (P > 0.05; Table 2). The mean blood pressure and heart rate at regular intervals after the spinal injection were also the same in all groups (P > 0.05).
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The postoperative pain data are described in Table 3. The VAS score at first rescue analgesic was the same among groups (P > 0.05). The time to first rescue analgesic was longer in the M/NG (683 ± 498 min) compared with the other groups (P < 0.05). The other groups were statistically similar (CG, 261 ± 87 min; MG, 428 ± 297 min; and NG, 363 ± 119 min; P > 0.05). The number of rescue analgesic injections (median, 25th–75th percentile) during the first 24 h after surgery was more in the CG (3 [2–4]) compared with the other groups (MG, 2 [1–2]; NG, 2 [1–2]; and M/NG, 1 [0–2]; P < 0.05). In the CG, apart from the ketoprofen consumption, two patients required additional dipyrone once, one patient twice, and another patient three times in 24 h. In the NG, apart from the ketoprofen, one patient required additional dipyrone twice and the other three patients once. In both the MG and M/NG, one patient requested dipyrone once apart from the ketoprofen. The overall 24-h pain VAS score was similar among groups (P > 0.05).
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There were no differences regarding the incidence of perioperative adverse effects. Intraoperatively, in the CG, one patient had hypotension followed by nausea, one patient had agitation, and another had bradycardia 30 min after the spinal block (40 bpm) and was treated with 750 µg of IV atropine. In the NG, one patient had hypotension followed by nausea, and another had bradycardia (44 bpm; 25 and 35 min after the spinal block). This last patient was treated with 1 mg of IV atropine. In the MG, one patient complained of pruritus, and another patient had vomited twice 65 and 70 min after the spinal block. In the M/NG, no adverse effects were observed. Postoperatively, two patients from the NG had vomited once 180 min and 245 min after the spinal block, and this was self-limited. In the MG, one patient had pruritus, five patients complained of urinary retention, and three of these patients required a urinary catheter. In the M/NG, two patients complained of urinary retention.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The results obtained are in accordance with the literature related to the expected analgesic effect between the spinal opioid and the cholinesterase inhibitor, as demonstrated using an intrathecal administration (6,11,12). However, this is the first evaluation of the analgesic efficacy after the epidural route of administration of morphine and neostigmine in acute post-operative pain; previous work has studied chronic cancer pain (13). Most importantly, the difference between the intrathecal and epidural administration of morphine/neostigmine was that although nausea and vomiting were distressing side effects after the intrathecal route, no adverse effects were noted after the epidural administration in the population studied. The analgesic effect is secondary to (a) the direct action at the acetylcholinesterase and butyrylcholines-terase expressed at the spinal meninges, as demonstrated in monkeys (14) and (b) the drug spread into the cerebral spinal fluid (CSF) at approximately one tenth of the initial epidural dose administered (8). In contrast to the synergistic interaction between intrathecal neostigmine and IV alfentanil in relation to nausea (7), it seemed that the epidural route of administration has the benefit of a small incidence of nausea and vomiting, probably as a consequence of the small quantity of free neostigmine that crosses the spinal meninges and reaches the CSF.
Whereas neither 0.6 mg of epidural morphine nor 60 µg of epidural neostigmine resulted in postoperative analgesia by themselves, the combination of both drugs increased more than twice (11 hours compared with four hours in the CG) the time to first rescue analgesics after knee orthopedic surgery without increasing the incidence of undesirable side effects such as nausea and vomiting. The small doses of epidural morphine and epidural neostigmine alone revealed a trend towards analgesia, although it was not statistically significant compared with the CG (seven and six hours, respectively, compared with four hours in the CG). Of interest, the analgesic postoperative consumption in both the MG and NG was smaller compared with the CG, which reinforces the trace of analgesia observed clinically.
Nevertheless, the absence of evident analgesia with either drug alone and the perioperative adverse effects after morphine such as pruritus and urinary retention followed by the need for a urinary catheter were qualitatively distressing to the patients and to the surgeon. The vomiting observed in a few patients after surgery was short lived. The emetic effect of intrathecal neostigmine has been demonstrated to be secondary to the cephalic spread of the drug into the CSF (15).
In conclusion, we have demonstrated that the analgesic effect of the epidural route of administration after the combination of morphine and neostigmine via the intrathecal route resulted in analgesia that was devoid of distressing side effects such as nausea and vomiting, suggesting a potential role for the epidural route of administration of morphine/neostigmine in acute postoperative pain.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- Lauretti GR, Reis MP. Postoperative analgesia and antiemetic efficacy after intrathecal neostigmine in orthopedic surgery. Reg Anesth 1997; 22: 337–42.[Medline]
- Liu SS, Hodgson PS, Moore JM, et al. Dose-response effects of spinal neostigmine added to bupivacaine spinal anesthesia in volunteers. Anesthesiology 1999; 90: 710–7.[Web of Science][Medline]
- Kruskowski JA, Hood DD, Eisenach JC, et al. Intrathecal neostigmine for post cesarean section analgesia: dose response. Anesth Analg 1997; 84: 1269–75.[Abstract]
- Lauretti GR, Hood DD, Eisenach JC, Pfeifer BL. A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy. Anesthesiology 1998; 89: 913–8.[Web of Science][Medline]
- Rauck RL, Raj PP, Knarr DC, et al. Comparison of the efficacy of epidural morphine given by intermittent injection or continuous infusion for the management of postoperative pain. Reg Anesth 1994; 19: 316–24.[Medline]
- Klamt JG, Prado WA, Garcia LV. Analgesic and adverse effects of a low dose of intrathecally administered hyperbaric neostigmine alone or combined with morphine in patients submitted to spinal anaesthesia: pilot studies. Anaesthesia 1999; 54: 27–31.[Web of Science][Medline]
- Hood DD, Mallak KA, James RL, et al. Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition. J Pharmacol Exp Ther 1997; 282: 86–92.
[Abstract/Free Full Text] - Lauretti GR, Oliveira R, Reis MP, et al. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999; 90: 1534–8.[Web of Science][Medline]
- Lauretti GR, Oliveira R, Perez MV, Paccola CJ. Postoperative analgesia by intra-articular and epidural neostigmine following knee surgery. J Clin Anesth 2000; 12: 444–8.[Web of Science][Medline]
- Nakayama M, Ichinose H, Nakabayashi K, et al. Analgesic effect of epidural neostigmine after abdominal hysterectomy. J Clin Anesth 2001; 13: 86–9.[Web of Science][Medline]
- Lauretti GR, Reis MP, Prado WA, Klamt JG. Dose response study of intrathecal morphine versus intrathecal neostigmine, their combination, or placebo for postoperative analgesia in patients undergoing anterior and posterior vaginoplasty. Anesth Analg 1996; 82: 1182–7.[Abstract]
- Nelson KE, Dángelo R, Foss ML, et al. Intrathecal neostigmine and sufentanil for early labor analgesia. Anesthesiology 1999; 91: 1293–8.[Web of Science][Medline]
- Lauretti GR, Gomes JMA, Reis MP, et al. Low doses of epidural ketamine or neostigmine, but not midazolam, improve morphine analgesia in epidural terminal cancer pain therapy. J Clin Anesth 1999; 11: 663–8.[Web of Science][Medline]
- Ummenhofer WC, Brown SM, Bernards CM. Acetylcholinesterase and butyrylcholinesterase are expressed in the spinal meninges of monkeys and pigs. Anesthesiology 1998; 88: 1259–65.[Web of Science][Medline]
- Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine in humans. Anesthesiology 1995; 82: 331–43.[Web of Science][Medline]
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