Addition of Neostigmine or Fentanyl to Bupivacaine for patient-controlled epidural analgesia during labor did not reduce Bupivacaine requirement.

A combination of local anesthetic and an adjuvant opioid have been considered as an epidural infusion for labor analgesia. When an opioid is added to the epidural local anesthetic, the dose of local anesthetic is reduced which ultimately lessens the side effects from the local anesthetic blockade. However, these epidural opioids may also produce side effects like pruritus and decreased fetal heart rate variability. The side effects become the main reason for the shift in focus towards non-opioid adjuvants. Neostigmine, a cholinesterase inhibitor, produces analgesia when administered via the intrathecal or epidural route. Several studies conducted in the mid to late 1990s have showed the analgesic efficacy of intrathecal Neostigmine along with dose-dependent severe nausea and vomiting and further clinical development were discontinued. Also, epidural administration of Neostigmine was presented in both adults and children to decrease local anesthetic requirements in the postoperative setting without nausea and vomiting. In some small studies, epidural Neostigmine was shown to reduce the epidural local anesthetic requirement for labor analgesia to a point similar to that of opioids, including a study in which epidural analgesia was titrated via patient-controlled epidural analgesia (PCEA).

Rationale behind the research:

There is a lack of large randomized controlled studies evaluating the effects of epidural Neostigmine as an adjunct to local anesthetics in the obstetric population for continuous PCEA during labor.

Objective:

To examine the outcomes of epidural Neostigmine, 2, 4, or 8 μg/mL, with that of a commonly used concentration of Fentanyl (2μg/mL) when added to 0.125% Bupivacaine via PCEA during labor.

Outcome measures:

Primary Outcome: Total hourly local anesthetic consumption, defined as total patient-controlled epidural analgesia use and top-ups (expressed as milliliters of 0.125% Bupivacaine) divided by the infusion duration.

• Pain was evaluated on a 0 to 10 verbal scale.
• Other Parameters: Dermatomal level of sensory blockade to pinprick testing, degree of motor block on a 0 to 3 scale, maternal self-report of sedation (0 to 10), intensity of nausea (0 to 10), pruritus (0 to 10), and sleepiness (0 to 10), an observer's assessment of maternal alertness14 (1 to 5), and presence of shivering. Maternal hypotension (20% change or higher from baseline and/or requiring treatment), maternal bradycardia (maternal heart rate less than 60 beats/ min or higher than 20% decrease from the patient's baseline heart rate), fetal heart rate abnormalities, mode of delivery, and 1- and 5-min Apgar scores were recorded. The total volume of study solution administered, the number of PCEA demand boluses and the number and volume of anesthesiologist-administered Bupivacaine 2.5-mg/mL bolus doses were recorded after termination of the PCEA infusion. After delivery, patients also were asked to rate their overall degree of epidural labor analgesia using a 1 to 5 verbal score (1=not satisfied at all, 5=extremely satisfied).

Time Points:

• Pain: Before epidural catheter placement, immediately after combined subarachnoid/intravenous test dose, every 5 min for 20 min after initial epidural bolus of the study solution, and then every 2 h until delivery
• Other Parameters: Every 2 h until delivery
  

Study outcomes:

Baseline Characteristics: There were no baseline differences in the four study groups.

Primary Outcome: There was no difference in median hourly Bupivacaine use in PCEA, supplemental boluses, or their combination. The median hourly total Bupivacaine consumption of patients in the Fentanyl group was 16mL/h, and in Neostigmine 2, 4, and 8 μg/mL groups were 15.3, 14.6, and 16.2mL/h, respectively (P=0.55). The median hourly Bupivacaine consumption of patients from only the PCEA pump was 14.8mL/h in the Fentanyl group and 13.3, 12.6, and 13.0mL/h in the 2, 4, and 8 μg/mL epidural Neostigmine groups, respectively (P=0.25). The duration of complete study epidural labor analgesia was nonsignificant among groups (P=0.69). Also, there was no difference among groups in a number of patients requiring additional Bupivacaine boluses for improved labor analgesia (P=0.93).

Figure 1: Median hourly total Bupivacaine consumption of patients

• Mean pain scores during labor did not differ between the groups over time. Pain scores improved in all four groups after epidural placement
• Overall patient satisfaction with labor analgesia did not differ among groups (P=0.82).The overall median satisfaction score was 4.0 (very satisfied). No significant difference in Apgar scores at 1 and 5 min or cesarean delivery rate (P=0.84) was found.
• Epidural Neostigmine at any dose did not cause higher intensity scores than epidural Fentanyl of undesired side effects such as maternal nausea (P=0.66), sedation (P=0.64), shivering (P=0.40), or degree of the motor blockade (P=0.33). Average maximum pruritus scores of patients in the epidural Fentanyl group were considerably greater than patients receiving epidural Neostigmine (P=0.001). The four groups did not vary in the percentage of motor blockade, maternal self-assessment of nausea, maternal self-assessment of sleepiness, or pruritus over time.
  

The present study did not support any change in Bupivacaine requirements for labor patient-controlled epidural analgesia whether patients receive Neostigmine or Fentanyl.

Previous studies have shown an improvement in postoperative analgesia in both adults and children with epidural Neostigmine compared with epidural local anesthetic alone. However, this study did not find a clinical difference with epidural Neostigmine compared with epidural Fentanyl when combined with Bupivacaine for labor analgesia. Though additional studies are needed to evaluate the clinical safety of Neostigmine as well as the clinical effect of lower doses of epidural Neostigmine on labor analgesia, the possibility of futures studies is decreased by the repeated incapability to obtain Neostigmine from the manufacturer due to production shortages, the cost of Neostigmine, and lack of evidence showing a significant clinical effect compared with epidural Fentanyl.