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Anesth Analg 2003;96:1161-1166 © 2003 International Anesthesia Research Society
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Abstract |
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Spinal neostigmine produces analgesia without respiratory depression or hypotension but provokes major gastrointestinal side effects. Epidural injection of this drug, however, appears to induce analgesia devoid of such side effects. In this study, we evaluated the effect of a bolus of epidural neostigmine on the duration and magnitude of analgesia in early labor and assessed its eventual sparing effect on subsequent local anesthetic requirements. Epidural neostigmine methylsulfate (maximal dose 4 µg/kg) was added to 10 mL of ropivacaine 0.1%, with and without sufentanil 10 µg, to initiate analgesia. Twenty minutes after injection, pain score, sensory level, and motor block were assessed. Time until request for supplemental epidural medication was also recorded. Patient-controlled epidural analgesia with ropivacaine 0.1% was used for epidural supplementation. Maternal and fetal side effects were closely recorded. Neostigmine (4 µg/kg), when added to ropivacaine 10 mg, provided equivalent analgesia to ropivacaine 20 mg but was less effective than sufentanil 10 µg for the initiation of labor epidural analgesia. Further, neostigmine did not modify the subsequent patient-controlled epidural analgesia local anesthetic requirements during labor. No hemodynamic instability, additional motor block, or bothersome side effects were recorded.
IMPLICATIONS: The combination of epidural neostigmine (4 µg/kg) with the local anesthetic ropivacaine, with or without sufentanil, does not significantly enhance neuraxial analgesia during labor. Such a dose, however, has no bothersome side effects.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The current practice in obstetric anesthesia is often to combine small doses of an epidural local anesthetic with an adjuvant drug to produce selective analgesia, e.g., good pain relief with minimal motor blockade. Opioids are often used as adjuvants. Other substances, however, including the adrenergic agonists epinephrine or clonidine, have also been administered. Cholinesterase inhibitors, which inhibit the breakdown of endogenous acetylcholine and thus indirectly stimulate both muscarinic and nicotinic receptors, induce spinal analgesia in animals, volunteers, and patients. After safety assessment in volunteers (1), intrathecal neostigmine methylsulfate was introduced for perioperative pain relief (2–4) . Neostigmine produces a dose-independent analgesia without respiratory depression or hypotension and potentiates common spinal analgesics, such as local anesthetics and opiates (3,5) . Unfortunately, after intrathecal injection, severe gastrointestinal side effects (nausea and vomiting, diarrhea) occur and thus limit its routine clinical use. A few reports have evaluated the intrathecal administration of neostigmine in obstetrics, either for labor analgesia (6–8) or for pain relief after cesarean delivery (5,9) .
In contrast, epidural injection does not appear to be associated with these side effects (10,11) . It has been reported that epidural neostigmine produces postoperative analgesia lasting for several hours, as well as a significant opioid-sparing effect (10). Furthermore, one report suggesting a sex difference in cholinergic analgesia, in favor of females, illustrates another potential advantage of this drug for gynecologic surgery or obstetric analgesia (12). Therefore, we undertook this study to evaluate the use of epidural neostigmine in laboring women. We first attempted to evaluate whether there is a benefit of combining neostigmine with a local anesthetic, sufentanil, or both to initiate epidural analgesia during early labor. Because of safety concerns, although some authors have administered epidural injection of doses as large as 10 µg/kg (11), we opted to administer smaller doses of neostigmine (maximum dose of 4 µg/kg), because these doses have been given without significant adverse effects (10). We chose to use ropivacaine as a local anesthetic because of its greater safety profile and decreased propensity for motor block. Ropivacaine has already been broadly studied during labor, with both top-up dose injections (13) and patient-controlled epidural analgesia (PCEA) (14). We evaluated the effectiveness of epidural neostigmine plus ropivacaine for the initiation of analgesia (duration of top-up dose and efficacy) in early labor, with and without sufentanil. In addition, we assessed the effect of a single epidural bolus of neostigmine on subsequent ropivacaine requirements. Side effects were closely recorded in both mothers and fetuses throughout the labor.
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Methods |
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After approval by the Clinical Research Practices Committee and obtaining informed consent, ASA physical status I and II healthy parturients requesting epidural analgesia during labor were enrolled in the study. Lumbar epidural puncture was performed with a 18-gauge Tuohy needle, and an epidural catheter was inserted 4 cm at the L3-4 level in all parturients. Exclusion criteria included parturients with obstetric complications (multiple pregnancy, premature labor, or nonvertex presentation) or contraindications to regional analgesia. Accidental dural puncture when the epidural was performed also excluded patients from participation in the study. All parturients were in established labor when the epidural technique was performed, and all received an oxytocin infusion during the course of labor.
Pain was assessed with a 10-cm Visual Analog Scale (VAS). When the VAS score reached the level of 30 (out of 100), a test dose of 3 mL of lidocaine 2% with epinephrine 1:200,000 was administered via the catheter, after which the parturients were randomly allocated to one of the study groups. Patients in the first group received ropivacaine 0.2% 10 mL (ROPI 20; n = 20). This dose was chosen based on the reported ropivacaine 50% effective dose required to initiate epidural analgesia in early labor (7). In the other groups, 10 mL of ropivacaine 0.1% was combined with sufentanil 10 µg (ROPI 10 Suf; n = 22), sufentanil 10 µg and neostigmine 2 µg/kg (ROPI 10 Suf N2; n = 20), sufentanil 10 µg and neostigmine 4 µg/kg (ROPI 10 Suf N4; n = 23), or neostigmine 4 µg/kg (ROPI 10 N4; n = 20). Neostigmine was provided from the commercial solution of neostigmine methylsulfate (Prostigmine®, 0.5 mg/mL; Roche, Summerville, NJ), for which intrathecal safety assessment has been reported (1). All the parturients received the first epidural bolus in a total volume of 14 mL. The data were collected by an anesthesiologist—either a resident or an attending—who was blinded to the patient group.
Maternal noninvasive blood pressure, heart rate, and oxygen saturation were monitored. Fetal heart rate was also continuously recorded on a cardiotocograph. Twenty minutes after the epidural injection, the quality of analgesia provided by the different solutions was evaluated as follows: VAS score, level of sensory block by using the ether test, and motor block in the lower limb by using a modified Bromage scale (1 = complete motor blockade; 2 = almost complete motor blockade [the patient is able only to move the feet]; 3 = partial motor blockade [the patient is able to move the knees]; 4 = detectable weakness of hip flexion [the patient is able to raise the leg but is unable to keep it raised]; 5 = no detectable weakness of hip flexion [the patient is able to keep the leg raised during 10 s at least]; 6 = no weakness at all). The duration of analgesia was considered as the time elapsed to the patient’s first request for further analgesia (new epidural injection because of VAS 
30 out of 100). From this moment, epidural catheters were connected to a PCEA device (Pancretec® Provider 5500; Abbott, North Chicago, IL) with 0.1% ropivacaine. The PCEA was programmed with a basal infusion rate of 8 mL/h, supplemented with boluses of 5 mL available every 30 min. In case of inadequate analgesia, additional rescue doses of 5 to 10 mL of ropivacaine 0.1% were administered by the anesthesiologist until the parturient reached an acceptable level of comfort (VAS 
30 out of 100).
The total duration of the labor from the time of the first epidural injection until delivery, the hourly ropivacaine use during the course of labor, the number of supplemental doses of local anesthetic administered by the anesthesiologist as rescue analgesia, and the supplemental dose necessary at the time of delivery were recorded. Mode of delivery—normal vaginal and instrumental—was also reported. Maternal adverse effects (nausea and vomiting, sedation) and fetal side effects (bradycardia during labor and low Apgar scores) were recorded.
A prospective sample size calculation (STATISTICA, StatSoft, Tulsa, OK) indicated that 20 subjects were required in each group to have an 80% power to detect a 25% difference at an 
level of 0.05 in both the duration of analgesia resulting from the first epidural bolus and the subsequent ropivacaine requirements during PCEA use.
Results were expressed as mean ± SD, 95% confidence interval, or median (interquartile range), as indicated. Demographic data and continuous variables were compared among the groups by analysis of variance, followed, if appropriate, by multiple comparisons with the Tukey honest significant different test (Statistica; StatSoft, Tulsa, OK). Comparison of ordinal categorical data among groups was realized by application of the Kruskal-Wallis test, followed by Wilcoxon’s ranked sum test for multiple comparisons. The 
2 test with the Yates correction was used to compare side effects. In general, P < 0.05 was considered significant.
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Results |
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One-hundred-one patients completed the study; six parturients (two in Group ROPI 10 Suf, three in Group ROPI 10 Suf N2, and one in Group ROPI 10 N4) were excluded because they underwent cesarean delivery. Variables including age, weight, and parity were similar among the groups, as was cervical dilation, which was between 3 and 5 cm at the time of neostigmine injection (Table 1).
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Maternal hemodynamic variables were similar in all groups and did not change after epidural injection in any group. Furthermore, the administration of neostigmine (2 and 4 µg/kg) was devoid of significant effects on maternal blood pressure or heart rate during the first 20 min postinjection (Table 2) and also throughout labor. Fetal heart rate also remained stable until the completion of analgesic effect and then throughout the duration of labor. Initial VAS values did not differ among the groups. All epidural injections provided efficient analgesia and significantly reduced the initial VAS (Table 3). After 20 min, the best pain relief (in terms of VAS reduction) was obtained with the combination of neostigmine 4 µg/kg/sufentanil/ropivacaine 10 mg (when compared with either ropivacaine 20 mg or ropivacaine 10 mg/neostigmine 4 µg/kg; P < 0.001). The level of sensory block did not differ among the groups (median level T8-9) even after the addition of neostigmine. The addition of epidural neostigmine to ropivacaine 10 mg did not significantly enhance the degree of motor block resulting from epidural ropivacaine 10 mg alone (P > 0.05 among all the ropivacaine 10 mg groups) (Table 3). Neostigmine 4 µg/kg added to ropivacaine 10 mg provided epidural analgesia of similar magnitude and duration to ropivacaine 20 mg, but with less motor block; however, in terms of potency and duration of epidural analgesia, neostigmine 4 µg/kg was less effective than sufentanil 10 µg when combined with ropivacaine 10 mg (Table 3).
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The administration of a single dose of epidural neostigmine did not significantly change the use of the PCEA system during labor (Table 4). Hourly ropivacaine consumption did not statistically differ among the groups, nor did the percentage of patients requesting rescue analgesia or a supplemental dose at delivery.
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At the doses of neostigmine that were used in this study, no major side effects, such as excessive sedation or nausea and vomiting, were recorded in any treatment group at any time during the course of labor. The addition of the cholinesterase inhibitor did not seem to interfere with the total duration of labor, nor did it affect the mode of delivery (Table 4). No harmful side effects, e.g., bradycardia, were noted in fetuses during labor, and Apgar scores did not differ among the groups (Table 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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These data suggest that epidural administration of neostigmine, in doses of up to 4 µg/kg, is not associated with serious side effects in laboring women and seems safe for fetuses. To initiate epidural analgesia in early labor, neostigmine 4 µg/kg combined with ropivacaine 10 mg produces neuraxial analgesia similar to that with ropivacaine 20 mg but with less motor block. However, at that dose, neostigmine is inferior to sufentanil 10 µg in terms of the magnitude and duration of analgesic effect. Furthermore, a single bolus of neostigmine does not reduce the subsequent requirements for local anesthetic administered by PCEA during labor.
Since the first safety reports on the spinal administration of neostigmine methylsulfate (1), only a few studies have described its use for obstetric analgesia. Intrathecal neostigmine was evaluated in the context of postcesarean delivery (5,9) and during early labor, alone or as a part of a local anesthetic, opioid, and 2-adrenergic agonist mixture (6–8) . However, a major barrier to further investigations was the incidence of gastrointestinal side effects (nausea and vomiting, diarrhea) related to spinal administration, even at doses as small as 10 µg (7,8) . Lauretti et al. (10) reported an analgesic effect devoid of these undesirable side effects after epidural neostigmine in postoperative patients. Our study is the first report that evaluates the potential benefits of an epidural cholinesterase inhibitor for labor analgesia.
At the same doses that provided analgesia and an opioid-sparing effect in perioperative acute pain conditions (10), i.e., 2 and 4 µg/kg, we did not observe a major potentiation of epidural analgesia and found decreased efficacy compared with the addition of sufentanil 10 µg. Although a long-lasting duration of spinal effect was reported both in volunteers (three to six hours) (1) and in postoperative patients (longer than four hours) (3,5,9,11) , in this study we did not find a significant sparing effect of a single equivalent dose on global local anesthetic requirements during labor.
Several factors may explain why our results contrast with previous reports on the epidural analgesic effect of neostigmine in postoperative pain (10,11) . First, early labor is described mainly as a model of visceral pain. Previous studies evaluating spinal neostigmine suggest that the drug is more effective for relieving somatic than visceral pain (2,3) . Labor pain, therefore, might not be the ideal situation in which to use an indirectly acting cholinergic drug. Moreover, because neostigmine is a hydrophilic substance, approximately one tenth of the epidural dose penetrates into the cerebrospinal fluid and spinal cord to provide effective analgesia (10). Hence, it may be that our patients really received a dose equivalent to 15 to 30 µg of intrathecal neostigmine. When intrathecal neostigmine was administered alone, 10 µg was ineffective in early labor (6), whereas the same dose potentiated a mixture of intrathecal bupivacaine, opioid, and clonidine (7,8) . We also observed a substantial benefit of combining sufentanil and neostigmine with ropivacaine; this provided the best reduction of pain intensity during the initiation of epidural analgesia. Second, in many of the published studies evaluating epidural neostigmine, the analgesic effect was evaluated at the time of administration of the first dose of postoperative rescue analgesic. At that time, the painful stimulus (i.e., surgical manipulation) has already stopped. This represents a clinical situation very different from the conditions related to this study, in which parturients were experiencing increasing pain resulting from the progression of labor. Finally, it is possible that a larger dose of neostigmine would have produced a better effect. Other authors have reported that after abdominal hysterectomy, which presents a combination of both visceral and somatic nociceptive stimuli, epidural neostigmine 10 µg/kg enhanced the duration of postoperative analgesia, whereas a dose of 5 µg/kg remained ineffective (11). We chose to administer a smaller dose of neostigmine because in laboring women, fetal safety represents a major concern. Systemic resorption of neostigmine into the maternal circulation can occur after epidural administration and can produce fetal bradycardia by crossing the placenta and increasing fetal vagal tone (15).
As in previous studies, we did not observe undesirable side effects after the epidural administration of neostigmine. In particular, no hemodynamic instability was noted. This is not surprising, because spinal cholinesterase inhibitors may blunt local anesthetic-induced hypotension in animals and humans (4,8,10) . The lack of gastrointestinal side effects after epidural injection, as compared with the frequent rate of nausea, vomiting, and diarrhea observed after administration either intrathecally (4) or into the brachial plexus (16), is intriguing. Such findings reinforce the idea that analgesia from epidural neostigmine is mainly related to a spinal mechanism, although some supraspinal effect cannot be excluded. The role of the meninges in acetylcholine metabolism and their role in the analgesic effect of cholinesterase inhibitors demand further research (17).
A certain degree of motor weakness can result from intrathecal administration of cholinesterase inhibitors (1); it is related to an acetylcholine effect on the motor neuron that can potentiate the axonal conduction block caused by local anesthetics. In contrast with perioperative conditions, where muscle relaxation can be beneficial for surgery, motor weakness during labor analgesia is potentially problematic. At the doses used in this study, epidural neostigmine did not enhance motor block from local anesthetics, as was suggested in other studies (10,11) .
In conclusion, a single dose of epidural neostigmine (up to 4 µg/kg) does not appear to provide an analgesic benefit when combined with ropivacaine during labor. In contrast with spinally-administered neostigmine, no serious side effects, either in the mother or in the fetus, were observed. Further studies are necessary with larger doses of epidural neostigmine and an evaluation of possible synergy with other analgesics, as well as of the potential benefit of adding neostigmine into a PCEA or to a continuous-infusion solution.
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Acknowledgments |
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Supported by the Department of Anesthesiology of the University of Louvain, St. Luc Hospital.
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References |
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- Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1995; 82: 331–43.[Web of Science][Medline]
- Lauretti GR, Lima IC. The effects of intrathecal neostigmine on somatic and visceral pain: improvement by association with a peripheral anticholinergic. Anesth Analg 1996; 82: 617–20.[Abstract]
- Lauretti GR, Mattos AL, Reis MP, et al. Combined intrathecal fentanyl and neostigmine: therapy for postoperative abdominal hysterectomy pain relief. J Clin Anesth 1998; 10: 291–6.[Web of Science][Medline]
- 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]
- Chung CJ, Kim JS, Park HS, et al. The efficacy of intrathecal neostigmine, intrathecal morphine and their combination for post-cesarean section analgesia. Anesth Analg 1998; 87: 341–6.
[Abstract/Free Full Text] - Nelson KE, D’Angelo R, Foss M, et al. Intrathecal neostigmine and sufentanil for early labor analgesia. Anesthesiology 1999; 91: 1293–8.[Web of Science][Medline]
- Owen MD, Ozsarac O, Sahin S, et al. Low dose clonidine and neostigmine prolong the duration of intrathecal bupivacaine-fentanyl for labor analgesia. Anesthesiology 2000; 92: 361–6.[Web of Science][Medline]
- D’Angelo R, Dean LS, Meister G, Nelson KE. Neostigmine combined with bupivacaine, clonidine and sufentanil for labor analgesia. Anesth Analg 2001; 93: 1560–4.
[Abstract/Free Full Text] - Krukowski 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, de Olivera 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]
- 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]
- Chiari A, Tobin JR, Pan HL, et al. Sex differences in cholinergic analgesia. I. A supplemental nicotinic mechanism in normal females. Anesthesiology 1999; 91: 1447–54.[Web of Science][Medline]
- Lee BB, Ngan Kee WD, Wong EL, et al. Dose-response study of epidural ropivacaine for labor analgesia. Anesthesiology 2001; 94: 767–72.[Web of Science][Medline]
- Ruban P, Sia ATH, Chong JL. The effect of adding fentanyl to ropivacaine 0.125% on patient-controlled epidural analgesia during labor. Anaesth Intensive Care 2000; 28: 517–21.[Medline]
- Clark RB, Brown MA, Lattin DL. Neostigmine, atropine and glycopyrrolate: does neostigmine cross the placenta? Anesthesiology 1996; 84: 450–2.[Medline]
- Bouaziz H, Paqueron X, Bur ML, et al. No enhancement of sensory and motor blockade by neostigmine added to mepivacaine axillary plexus block. Anesthesiology 1999; 91: 78–83.[Web of Science][Medline]
- Ummenhoffer 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]
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